Role of intraoperative ultrasound and MRI to aid grade of resection of pediatric low-grade gliomas. Accumulated experience from 4 centers

Role of intraoperative ultrasound and MRI to aid grade of resection of pediatric low-grade gliomas. 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Accumulated experience from 4 centers Sofie Dietvorst, Armen Narayan, Cyril Agbor, Dawn Hennigan, David Gorodezki, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4644683/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Jul, 2024 Read the published version in Child's Nervous System → Version 1 posted 7 You are reading this latest preprint version Abstract Purpose Pediatric low-grade gliomas (pLGG) are the most common brain tumors in children and achieving complete resection (CR) is the most important prognostic factor. There are multiple intraoperative tools to optimise the extent of resection (EOR). This article investigates and discusses the role of intraoperative ultrasound (iUS) and intraoperative magnetic resonance imaging (iMRI) in the treatment of pLGG. Methods The tumor registries at Tuebingen, Rome and Pretoria were searched for pLGG with the use of iUS and data on EOR. The tumor registries at Liverpool and Tuebingen were searched for pLGG with the use of iMRI where preoperative CR was the surgical intent. Different iUS and iMRI machines were used in the 4 centers. Results We included 111 operations which used iUS and 182 operations using iMRI. Both modalities facilitated intended CR in hemispheric supra- and infratentorial location in almost all cases. In more deep seated tumor location like supratentorial midline tumors, iMRI has advantages over iUS to visualize residual tumor. Functional limitations limiting CR arising from eloquent involved or neighboring brain tissue apply to both modalities in the same way. In the long-term follow-up, both iUS and iMRI show that achieving a complete resection on intraoperative imaging significantly lowers recurrence of disease (Chi-square test, p < 0.01). Conclusion iUS and iMRI have specific pros and cons, but both have been proven to improve achieving CR in pLGG. Due to advances in image quality, cost- and time-efficiency, and efforts to improve the user interface, iUS has emerged as the most accessible surgical adjunct to date to aid and guide tumor resection. Since the EOR has the most important effect on long term outcome and disease control of pLGG in most locations, we strongly recommend taking all possible efforts to use iUS in any surgery, independent of intended resection extent, and iMRI if locally available. Pediatric low-grade glioma extent of resection intraoperative ultrasound intraoperative MRI Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Brain cancers are the most common solid tumors in children and lead to more years of life lost than other more common cancers. Therefore, improving outcomes for brain cancer is still, despite significant advances in the last decades, an unmet clinical need.( 1 ) Low-grade gliomas (LGG) are the most frequent pediatric brain tumors and comprise multiple entities. Surgery is the first line of treatment in the majority, and the extent of resection (EOR) is the most important modifiable prognostic factor, such that prognosis and long-term outcome in patients who have had gross total resection (GTR) is better than those with incomplete resection.( 2 , 3 ) It is important to emphasize that that pediatric LGG (pLGG) are a different collection of tumors than adult LGG, with different underlying molecular genetic characteristics.( 2 , 4 , 5 ) Compared to adults, pLGG have lower rates of conversion to malignant tumors and have a low incidence of glioma related death. Secondly, treatment with radiation therapy can lead to inferior long-term outcomes.( 2 , 6 ) The primary goal in pLGG surgery is complete resection (CR) whilst preserving brain function. The latter is of utmost importance since the overall survival rates in pLGG patients are high and therefore functional impairments as the consequence of treatment have a long-lasting impact on the quality of life of the affected children and adolescents.( 6 ) There are multiple aids to aim for CR. The use of intraoperative neuronavigation is one of them, but this is considered a major advantage for location of the bone flap and trajectory planning rather than for completeness of resection of tumor. As the tumor is removed the brain also moves (‘brain shift’) which makes the technology to define the tumor margins at the end of surgery in many instances highly inaccurate. The gold standard to assess for complete tumor removal is the early post-operative MRI (done 1–2 days after surgery). Most accurate for this purpose is the 3 months post-operative MRI scan when all surgery induced tissue changes or tumor related non tumorous changes like edema have completely disappeared. Patients with residual tumor might need a second operation to complete the resection in case of regrowth originating from this residual.( 7 ) To render surgery as effective as possible regarding completeness of tumor removal, intraoperative ultrasound (iUS) is the most commonly available intraoperative tool delivering real-time images during the surgery enabling the surgeon to localize the tumor, assess vascularity and determine the tumor margins and degree of resection.( 8 , 9 ) The benefits of being relatively cost effective, portable, radiation-free and providing real-time feedback have made this tool a very attractive option. There are however limitations regarding technology, such as quality of machine algorithms to produce images, quality of ultrasound transducer, distance of tumor to probe, artifacts introduced by surgery or resection cavity and experience of surgeon in interpretation of images, which are influencing the results and abilities of iUS.( 10 ) Developments and advances in iUS equipment and software continue to make this modality more appealing. Several retrospective studies have shown good concordance with the post-operative MRI but only in selected tumor types and locations.( 11 – 13 ) The gold standard for intraoperative imaging is the use of intraoperative MRI (iMRI), where an MRI is done while surgery is paused, with the possibility to proceed with the operation if residual tumor is detected and the functionality/eloquence of the brain next to the tumor allows for further resection. However, iMRI is not available to most children treated for pLGG. It involves a high initial investment in machinery and there is a specific set-up of operative environment, with prolonged operating time and a higher number of staff to achieve the goal of improved resection. In one series ~ 28% of all pediatric tumor resections with iMRI received immediate further resection. This delivered GTR in > 95% of patients but added 2-4hours to the operation time.( 14 ) In a specific analysis of iMRI in pLGG resection the use of iMRI increased the rate of intended GTR from 41–71% compared to the cohort prior to introduction of iMRI and the remaining residual tumor volume was significantly lower.( 15 ) A Cochrane review highlighted a lack of good quality evidence to support the use of any particular intraoperative imaging technology over another.( 16 ) There was poor quality evidence regarding which technologies have the greatest efficacy and there was a lack of information about the impact on neurological function of more radical surgical resection. There are no ongoing or new trials evaluating iUS or iMRI that will influence treatment guidelines and policy. This article is intended to demonstrate and analyze the use and value of iUS or iMRI in the surgical treatment of pLGG patients based on accumulated experience from 4 large pediatric neuro-oncology centers across Europe and South Africa. All institutions are using iUS as routine with two centers having iMRI in routine use as well with sufficient previous experience in the field.( 9 , 10 , 14 , 15 ) Materials and methods Patients were included from the existing pediatric tumor registries in each hospital. The data were retrospectively collected and anonymized. All centers had institutional approval for retrospective data collection. For the iUS data, children aged 0–18 years were included when histological diagnosis of pLGG was confirmed after surgery, iUS was used for either location and/or extent of resection of the tumor. Inclusion was done at Fondazione Policlinico Universitario A. Gemelli Roma (Italy) from 2017 till 2023, Steve Biko Academic Hospital Pretoria (South-Africa) from 2020 till 2024 and Universitätsklinik Tuebingen (Germany) from 2014 till 2020. iUS was performed with MyLabTwice® microconvex probe (Esaote, Italy) in Roma; with Philips Epic Elite (Amsterdam, The Netherlands) probes L15-7io hockey stick and C8-5 curvilinear in Pretoria; and with Siemens Acuson (Siemens, Erlangen, Germany), BK5000 and BK Active, BK Medical, Copenhagen, Denmark) with linear 15 MHz Hockeystick probe and 10 MHz neurosurgery curvilinear probe in Tuebingen. In the Rome, Pretoria and Tuebingen iUS experience, iUS was methodically performed before opening the dura mater to assess the lesion site and its features. Brain parenchyma was insonated on standard planes repeatedly during different phases of tumor resection, and again once resection was completed and after dural closure, which could simplify the comparison with preoperative MRI. In addition, the Pretoria group’s imaging protocol also includes routinely performing ultrasound imaging of the optic nerve sheath at the beginning and at the end of the procedure. Concordance of iUS images with preoperative MRI is essential at this stage of surgery and may be time consuming, especially in early experience with iUS. In general, for frontal craniotomies coronal and sagittal planes are used, while coronal and axial planes are useful for temporal craniotomies. Usually, curved probes (5–8 MHz) are used for large and deep lesions, although they might lack resolution. On the other hand, linear probes (6–15 MHz) have higher spatial resolution and are used for small and superficial tumors.( 17 ) The curved array probe with a 14mm ray of curvature allows for imaging in smaller craniotomy access and the ability to change the focus of the ultrasound beam provides the combined advantage of using linear and phased-array probes. Additionally, hybrid systems using preoperative MRI and iUS data allows real-time neuronavigated iUS, thanks to a magnetic coregistration of preoperative MRI and iUS, that could further aid the interpretation of iUS and orientation of the surgeon. In deep-seated lesions, iUS was also used to guide the surgical trajectory. It is important to re-scan the operative field by iUS during the course of resection with known and visible residual tumor to monitor progress of resection, appearance of artifacts and their different appearance to confirmed residual tumor. This improves the surgeons orientation, gives her/him a feeling for the residual disease and thus improves assessment at the end. After the macroscopic complete resection of the lesion according to the microsurgical view, or at the end of intended subtotal resection to functional limitations, US was repeated to assess the EOR on the same planes explored before resection and concordance with postoperative MRI was defined, as described elsewhere.( 10 ) For the iMRI data, children aged 0–18 years were included when iMRI was used for resection control, histological diagnosis of LGG was confirmed after surgery, and preoperative intent of treatment was CR. Inclusion was done at Alder Hey Liverpool NHS trust (UK) from 2010 till 2023 and Universitätsklinik Tuebingen (Germany) from 2014 till 2020. iMRI was performed by 3T-MRI in Liverpool (Philips Healthcare, Amsterdam, the Netherlands) and by 1.5T-MRI in Tuebingen (Espree, Siemens Medical Systems). Imaging included the brain tumor protocol with T1, T2, FLAIR, DWI and contrast-enhanced images.( 18 , 19 ) The EOR on iMRI scan findings was based on evaluation performed in consensus by the radiologist and the operating neurosurgeon during iMRI acquisition. Variables that were reviewed included patient demographics, location of the tumor (supratentorial or posterior fossa), EOR, pathological diagnosis, and follow-up of tumor where available. Results Intraoperative ultrasound The iUS data of pLGG includes 111 operations in total (in 111 patients), 51 from Tuebingen, 35 from Rome and 25 from Pretoria. The details of these operations can be found in Table 1 . Patients included and analyzed contained all cases in a given time period, also those where subtotal resection due to functional limitations was the primary intention to treat. iUS was used for both purposes: to maximize the rate of CR in the group of patients where CR was the intention or to minimize the amount of residual tumor in the group where subtotal resection was the defined intention to treat. Two examples of peroperative imaging with iUS are demonstrated in Figs. 1 and 2 . Table 1. The combined data of resections of pLGG with use of iUS, gathered in three large pediatric neuro-oncology centres. The number of operations is divided into supratentorial (STT) or posterior fossa (PF) location. The extent of resection is divided into gross-total resection or incomplete resection, the number of operations as well as the percentage per centre are given. The median age in years is included. In the Tuebingen Cohort of 51 patients CR was the intent in 35 cases, STR due to obvious functional limitations in 16 patients, greatly depending on the anatomical region. Intraoperative neurophysiological monitoring was used if monitorable brain or brain stem function was involved at the site of surgery. In all 29 cases of supratentorial hemispheric and cerebellar hemispheric locations the intention to treat was CR. According to the reading of 3 months postoperative MRI, CR was reached in12/12 patients (supra-) and 15/17 patients (infratentorial). The remaining tissue volume in the 2 incomplete cerebellar cases was 0.1 ml and 0.4 ml respectively, therefore minimal. One was lost to follow-up, the other remained stable. In the 4th ventricle manifestations, CR was intended in 4 patients and only reached in 2 for functional reasons of ventricular floor infiltration. In all other locations (brainstem, supratentorial midline) we did define STR as goal of surgery, except for 2 cases in the thalamus. In one GTR was reached, in the other 6% of the tumor volume remained. The total number of patients in all locations with GTR was 30, follow-up was available for 29 patients. In two (6.9%) of these patients there was recurrence of disease. The US guided volume reduction in the 21 STR designed cases ranged from 22 to 98%, median 57% of initial tumor volume. Long-term follow-up regarding progression of residual disease after ultrasound guided resection was available for 18 patients with median follow-up 51months. In nine (50%) of these patients there was progression. These results are significantly different (Chi square test, p < 0.01). In the Rome Cohort CR was the intent of surgery in 24 out of 28 supratentorial and in 5 out of 7 infratentorial tumors. Similar to the Tuebingen experience, intended STR for supratentorial tumors was performed to avoid obvious functional limitations (e.g. optic pathway glioma) or in case of large tumors involving the region of thalamus and basal ganglia. In the posterior cranial fossa, STR was performed in two cases of brainstem exophytic gliomas while CR was achieved in all cases of cerebellar hemispheric gliomas. This was similar in the Pretoria experience, where a combined structural and functional monitoring approach was used for all hemispheric and posterior fossa tumors, i.e combining iUS guidance with intra-operative neurophysiological monitoring (IONM) to achieve the goal of maximal safe resection. In Rome, no cases of recurrence were recorded after CR guided by iUS so far, with median follow-up of 36 months. Overall, a total concordance of post-iUS to postoperative MRI was noted in Rome and Pretoria, although a detailed volumetric analysis of the residual tumor was not available for STR like for the Tuebingen cases. Interestingly, iUS was also able to detect intraoperative complications, such as a focal intraparenchymal hemorrhage secondary to brain collapse after the resection of a large intraventricular tumor. Intraoperative MRI The iMRI data of pLGG with intent of CR includes 182 operations in total, 164 operations (in 150 patients) from Liverpool and 18 operations (in 18 patients) from Tuebingen. The details of these operations can be found in Table 2. Two examples of peroperative imaging with iMRI are demonstrated in Figs. 3 and 4 . Table 2. The combined data of resections of pLGG with use of iMRI, gathered in two large pediatric neuro-oncology centres. The number of operations is divided into supratentorial (STT) or posterior fossa (PF) location. The extent of resection is divided into gross-total resection or incomplete resection, the number of operations as well as the percentage per centre are given. The median age in years is included. Long-term follow-up regarding progression/recurrence of resection with iMRI was available for both Liverpool and Tuebingen. In the Liverpool data, CR was achieved at time of the first iMRI in 77 operations (47%), without need for further resection. In 73 operations (44.5%) we proceeded with second look surgery, which led to CR in 59 operations (80.8% of second look operations). In 5 operations, CR was achieved but the images of iMRI were not useful due to technical difficulties (CR was confirmed on postoperative MRI in the first 48 hours). In the total cohort of Liverpool, CR was achieved in 141 patients (86%) confirmed by MRI. Incomplete resection was mainly due to invasion of eloquent areas (more specific brainstem or cerebellopontine angle in the posterior fossa, supratentorial in cerebral hemisphere). Long-term follow-up was available in 144 operations (87.8%) with median follow-up of 46 months. In the CR group, there was recurrence of disease in 18 cases (14.2%). In the incomplete resection group, there was progression in 10 cases (58.8%), which is significantly more than the CR group (Chi square test, p < 0.01). In the Tuebingen data, CR was achieved at time of the first iMRI in 4 operations (22.2%). In 14 operations (77.8%) we proceeded with second look surgery, which led to CR in 11 operations (78.6%). In the total cohort of Tuebingen, CR was achieved in 15 patients (83.3%) confirmed by MRI. Incomplete resection was mainly due to invasion of eloquent areas. Long-term follow-up was available in 17 operations (94.4%) with median follow-up of 61 months. In the CR group, there was recurrence of disease in 3 cases (21.4%). In the incomplete resection group, there was progression in one case (33.3%). These results are not significantly different (Chi square test, p 0.531). If we combine the long-term follow-up data of Liverpool and Tuebingen, in the group of CR there is recurrence of disease in 21 out of 141 cases (14.9%). In the incomplete resection group there is progression in 11 out of 20 cases (55%), which is significantly more than the CR group (Chi square test, p < 0.01). Discussion Optimizing the balance between extent of resection and preservation of neurological function remains the goal of brain tumor surgery. The value of structural monitoring during brain tumor surgery to contribute to this has been established in numerous studies.( 20 – 22 ) Our results present an overview of the use of perioperative imaging in all-day neurosurgery practice for pLGG, to optimize the extent of safe resection. There is a difference in the results of GTR in the iUS data from Tuebingen versus Roma/Pretoria. In the Tuebingen data, there were more posterior fossa medullar tumors included. Supratentorial there were multiple optic pathway gliomas included, which was different from the other centers, and there was no aim for GTR in these cases. For iMRI, there is a significant reduction in recurrence of pLGG when CR is confirmed on imaging in the Liverpool dataset. This was not significant in the Tuebingen data, but this was probably due to the relatively small sample size. The value of iUS for surgical-image guidance has enjoyed a tremendous upsurge in recent years. The real-time, portable, cost-effective benefits combined with the improved quality of imaging provided by modern probes has contributed to its increased utility in neurosurgery. First, it can be used to delineate and optimize the approach to the lesion, even before the dura is opened. Combining real-time iUS with neuronavigation, the last becoming less reliant during surgery due to resection and loss of cerebrospinal fluid, has further addressed some of the challenges limiting its widespread use. With the possibility of Doppler images in iUS, also blood vessels and flow are pictured which will help in the decision-making during resection.( 10 , 17 , 23 , 24 ) iUS is considered an accessible first step to implement in a pediatric neurosurgery unit as an anatomical perioperative monitoring tool. Furthermore, iUS may guide the surgical trajectory for deep-seated tumors and finally assess EOR. Assessment of EOR is affected by known limitations, that are largely described through literature. iUS features that define surgical margins as disease-free are unclear to date. Moreover, surgical artifacts may significantly hinder the assessment of surgical margins, in particular in large tumors with large cortical access and/or collapsed surgical cavity, as well as open ventricle. Several advances in the multiparametric application of ultrasound, which includes the use of ultrasound contrast agents (UCAs), ultrasound elastography, 3-dimensional navigated ultrasound and Doppler flow contribute significantly to improving the sensitivity of iUS for detecting residual tumor volume, though these modalities may not be available on many US systems and sufficient data on their use still does not exist in children. Despite these limitations, gaining experience with this technology may aid in defining surgical strategies or technical tricks to enhance the reliability of iUS.( 10 ) Thus, iUS is a versatile surgical adjunct with an important role during the different stages of surgery, though the present study, as most of the studies published in the literature so far, focuses on the role of iUS in aiding to achieve CR.( 25 , 26 )The above named advantages provided by using iUS, along with its ease-of-use and repeatability, is the main difference when compared to iMR. iUS may therefore significantly contribute to steepen the learning curve in tumor surgery of young surgeons and we are convinced it helps to perfect the CR rates of experienced surgeons in all superficial tumor locations not deeper than 5-6cm from the brain surface. iMRI has the advantages of higher resolution, less artefacts and being less dependent on the experience of the user. Especially in the deeper-seated locations, visualization with iMRI is better compared to iUS.( 27 ) The high initial cost of equipment and the time it adds to the operation with an extensive staff make it not widespread available.( 28 ) However, it has been proven that the use of iMRI reduces the need for early repeat surgery in pediatric brain tumors and that the perioperative images that confirm GTR pre-empt new postoperative MRI imaging.( 14 , 29 ) Also in MRI, there is a continuous evolution in advanced imaging, which contributes to safely maximise the level of resection.( 30 ) Conclusion Intraoperative ultrasound and MRI have specific pros and cons, but both have been proven to improve the extent of resection in pediatric low-grade gliomas. For iMRI, since this is a static tool, it can easily be proven on sequential imaging with extent of resection and recurrence of disease as shown in our results. This is more difficult for iUS as it is a dynamic tool which is user dependent. 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Neuroradiology 63(8):1367–1376 Mato D, Velasquez C, Gómez E, Marco de Lucas E, Martino J (2021) Predicting the Extent of Resection in Low-Grade Glioma by Using Intratumoral Tractography to Detect Eloquent Fascicles Within the Tumor. Neurosurgery 88(2):E190–202 Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.jpg Table 1. The combined data of resections of pLGG with use of iUS, gathered in three large pediatric neuro-oncology centres. The number of operations is divided into supratentorial (STT) or posterior fossa (PF) location. The extent of resection is divided into gross-total resection or incomplete resection, the number of operations as well as the percentage per centre are given. The median age in years is included. Table2.jpg Table 2. The combined data of resections of pLGG with use of iMRI, gathered in two large pediatric neuro-oncology centres. The number of operations is divided into supratentorial (STT) or posterior fossa (PF) location. The extent of resection is divided into gross-total resection or incomplete resection, the number of operations as well as the percentage per centre are given. The median age in years is included. Cite Share Download PDF Status: Published Journal Publication published 16 Jul, 2024 Read the published version in Child's Nervous System → Version 1 posted Editorial decision: Accepted 01 Jul, 2024 Reviews received at journal 29 Jun, 2024 Reviewers agreed at journal 28 Jun, 2024 Reviewers invited by journal 28 Jun, 2024 Editor assigned by journal 27 Jun, 2024 Submission checks completed at journal 27 Jun, 2024 First submitted to journal 26 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4644683","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":321330095,"identity":"558176a8-c92f-4588-9c7c-36f9613d8f7b","order_by":0,"name":"Sofie Dietvorst","email":"data:image/png;base64,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","orcid":"","institution":"Alder Hey Childrens Hospital NHS trust","correspondingAuthor":true,"prefix":"","firstName":"Sofie","middleName":"","lastName":"Dietvorst","suffix":""},{"id":321330097,"identity":"f2bc8faf-daa8-45a3-b51b-9512161759f4","order_by":1,"name":"Armen Narayan","email":"","orcid":"","institution":"University Hospital of Tuebingen","correspondingAuthor":false,"prefix":"","firstName":"Armen","middleName":"","lastName":"Narayan","suffix":""},{"id":321330098,"identity":"62f0443f-585a-469d-9776-659509ea0836","order_by":2,"name":"Cyril Agbor","email":"","orcid":"","institution":"Brain Tumor and Translational Neuroscience Centre","correspondingAuthor":false,"prefix":"","firstName":"Cyril","middleName":"","lastName":"Agbor","suffix":""},{"id":321330100,"identity":"5bd12a0c-bf38-4171-9c60-26ea4ac78f58","order_by":3,"name":"Dawn Hennigan","email":"","orcid":"","institution":"Alder Hey Childrens Hospital NHS trust","correspondingAuthor":false,"prefix":"","firstName":"Dawn","middleName":"","lastName":"Hennigan","suffix":""},{"id":321330101,"identity":"263bd0c9-d155-4ffe-9e6a-de23df9fa7f5","order_by":4,"name":"David Gorodezki","email":"","orcid":"","institution":"University Hospital of Tuebingen","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Gorodezki","suffix":""},{"id":321330106,"identity":"59bdd444-4d29-4bb1-b347-159c168a6b91","order_by":5,"name":"Federico Bianchi","email":"","orcid":"","institution":"Fondazione Policlinico Universitario A. Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Federico","middleName":"","lastName":"Bianchi","suffix":""},{"id":321330110,"identity":"3069c2c8-a1db-4f5e-9afb-9688651fc5b6","order_by":6,"name":"Conor Mallucci","email":"","orcid":"","institution":"Alder Hey Childrens Hospital NHS trust","correspondingAuthor":false,"prefix":"","firstName":"Conor","middleName":"","lastName":"Mallucci","suffix":""},{"id":321330112,"identity":"e90b2c4e-c377-493a-b76c-8fc1d9cc1f5e","order_by":7,"name":"Paolo Frassanito","email":"","orcid":"","institution":"Fondazione Policlinico Universitario A. Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Paolo","middleName":"","lastName":"Frassanito","suffix":""},{"id":321330113,"identity":"b14e1a1a-5b45-4bbe-85d0-7dc9ad17c779","order_by":8,"name":"Llewellyn Padayachy","email":"","orcid":"","institution":"Steve Biko Academic Hospital Pretoria, South-Africa","correspondingAuthor":false,"prefix":"","firstName":"Llewellyn","middleName":"","lastName":"Padayachy","suffix":""},{"id":321330114,"identity":"94458b30-325d-4fdd-828e-25c33cd29ded","order_by":9,"name":"Martin Ulrich Schuhmann","email":"","orcid":"","institution":"University Hospital of Tuebingen","correspondingAuthor":false,"prefix":"","firstName":"Martin","middleName":"Ulrich","lastName":"Schuhmann","suffix":""}],"badges":[],"createdAt":"2024-06-26 19:48:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4644683/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4644683/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00381-024-06532-3","type":"published","date":"2024-07-16T20:57:54+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60713116,"identity":"c68bce56-40bf-4032-8904-09a05f92b18e","added_by":"auto","created_at":"2024-07-19 20:32:24","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":125143,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003ePre- (A-B) and postoperative MRI (C-D) showing cerebellar pilocytic astrocytoma in a 16-year-old boy that was completely resected through suboccipital approach. Intraoperative US before resection showing a well-delineated hyperechoic tumor on axial and sagittal planes (E and F, respectively). Intraoperative US after resection of the tumor confirms CR on axial and sagittal planes (G and H, respectively). Note the concordance of iUS with the detail of the MRI (in the upper left angle of the image) that is oriented as iUS for the sake of interpretation.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure1rome.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4644683/v1/007d411ae4e798e3c18bf951.jpg"},{"id":60713718,"identity":"fc040a31-144b-4dcf-a0ae-b67853cd919a","added_by":"auto","created_at":"2024-07-19 20:40:24","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":98238,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003ePre- (A-B) and postoperative MRI (C-D) showing right parietal low-grade glioma in a 4-year-old boy that underwent partial resection guided by the intraoperative neurophysiological monitoring. iUS before resection showing the hyperechoic tumor with the superficial cystic portion (arrowhead) and faint margins of the deep component, on coronal and sagittal planes (E and F, respectively). iUS after partial resection showing the residual tumor (arrows) on coronal and sagittal planes (G and H, respectively).\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure2Rome.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4644683/v1/77fd58f399126a8002f66dc3.jpg"},{"id":60713117,"identity":"2dd43ab2-b742-41f2-85b2-2ac1c46ffc50","added_by":"auto","created_at":"2024-07-19 20:32:24","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":182761,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eA and B show the preoperative images with a large contrast-enhancing lesion in the fourth ventricle in a 15-year-old boy, histology confirmed a DNET. Figures C and D are the peroperative images that show a small persistent contrast-enhancing zone in the roof of the fourth ventricle. Figures E and F show the results after second look surgery with further resection of the tumor. Figures G and H are the latest available images postoperatively which show CR, done six years postoperatively.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure3liverpool.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4644683/v1/defc1cbf2d5dd17c7406576b.jpg"},{"id":60713119,"identity":"99144941-bbe0-4dd5-8220-8ad25c974326","added_by":"auto","created_at":"2024-07-19 20:32:24","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":139267,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eA and B show the preoperative images of an 8-year-old boy with a thalamic cystic contrast-enhancing lesion, histology confirmed a ganglioglioma. Figures C and D show the peroperative images done to assess the progress of resection of tumor, whereafter further resection was proceeded. Figures E and F are done at the end of surgery and show the EOR. CR was redeemed unsafe and a small deep-seated thalamic zone along the capsula interna was left in situ. Figures G and H show the last postoperative imaging done five years after surgery, which show that there is no progression of disease.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure4liverpool.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4644683/v1/1b05c54649aebbfd8c310094.jpg"},{"id":60714112,"identity":"d56cc30c-b518-4fef-8d66-c6cbe06a9776","added_by":"auto","created_at":"2024-07-19 20:57:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":882012,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4644683/v1/f973c66f-dec9-4b07-8375-c0ceb9dcce36.pdf"},{"id":60713114,"identity":"c1c44572-6108-4fda-8667-60ef4b0380e2","added_by":"auto","created_at":"2024-07-19 20:32:24","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":32919,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eTable 1. The combined data of resections of pLGG with use of iUS, gathered in three large pediatric neuro-oncology centres. The number of operations is divided into supratentorial (STT) or posterior fossa (PF) location. The extent of resection is divided into gross-total resection or incomplete resection, the number of operations as well as the percentage per centre are given. The median age in years is included.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Table1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4644683/v1/b47aa455eabaf25cb6fb1d1d.jpg"},{"id":60713717,"identity":"10ebce83-5e64-452a-9003-fd7f8926848a","added_by":"auto","created_at":"2024-07-19 20:40:24","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":24452,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eTable 2. The combined data of resections of pLGG with use of iMRI, gathered in two large pediatric neuro-oncology centres. The number of operations is divided into supratentorial (STT) or posterior fossa (PF) location. The extent of resection is divided into gross-total resection or incomplete resection, the number of operations as well as the percentage per centre are given. The median age in years is included.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Table2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4644683/v1/a77389eb72c0895f0b51a7fd.jpg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Role of intraoperative ultrasound and MRI to aid grade of resection of pediatric low-grade gliomas. Accumulated experience from 4 centers","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBrain cancers are the most common solid tumors in children and lead to more years of life lost than other more common cancers. Therefore, improving outcomes for brain cancer is still, despite significant advances in the last decades, an unmet clinical need.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Low-grade gliomas (LGG) are the most frequent pediatric brain tumors and comprise multiple entities. Surgery is the first line of treatment in the majority, and the extent of resection (EOR) is the most important modifiable prognostic factor, such that prognosis and long-term outcome in patients who have had gross total resection (GTR) is better than those with incomplete resection.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) It is important to emphasize that that pediatric LGG (pLGG) are a different collection of tumors than adult LGG, with different underlying molecular genetic characteristics.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Compared to adults, pLGG have lower rates of conversion to malignant tumors and have a low incidence of glioma related death. Secondly, treatment with radiation therapy can lead to inferior long-term outcomes.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) The primary goal in pLGG surgery is complete resection (CR) whilst preserving brain function. The latter is of utmost importance since the overall survival rates in pLGG patients are high and therefore functional impairments as the consequence of treatment have a long-lasting impact on the quality of life of the affected children and adolescents.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThere are multiple aids to aim for CR. The use of intraoperative neuronavigation is one of them, but this is considered a major advantage for location of the bone flap and trajectory planning rather than for completeness of resection of tumor. As the tumor is removed the brain also moves (\u0026lsquo;brain shift\u0026rsquo;) which makes the technology to define the tumor margins at the end of surgery in many instances highly inaccurate. The gold standard to assess for complete tumor removal is the early post-operative MRI (done 1\u0026ndash;2 days after surgery). Most accurate for this purpose is the 3 months post-operative MRI scan when all surgery induced tissue changes or tumor related non tumorous changes like edema have completely disappeared. Patients with residual tumor might need a second operation to complete the resection in case of regrowth originating from this residual.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eTo render surgery as effective as possible regarding completeness of tumor removal, intraoperative ultrasound (iUS) is the most commonly available intraoperative tool delivering real-time images during the surgery enabling the surgeon to localize the tumor, assess vascularity and determine the tumor margins and degree of resection.(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) The benefits of being relatively cost effective, portable, radiation-free and providing real-time feedback have made this tool a very attractive option. There are however limitations regarding technology, such as quality of machine algorithms to produce images, quality of ultrasound transducer, distance of tumor to probe, artifacts introduced by surgery or resection cavity and experience of surgeon in interpretation of images, which are influencing the results and abilities of iUS.(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) Developments and advances in iUS equipment and software continue to make this modality more appealing. Several retrospective studies have shown good concordance with the post-operative MRI but only in selected tumor types and locations.(\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe gold standard for intraoperative imaging is the use of intraoperative MRI (iMRI), where an MRI is done while surgery is paused, with the possibility to proceed with the operation if residual tumor is detected and the functionality/eloquence of the brain next to the tumor allows for further resection. However, iMRI is not available to most children treated for pLGG. It involves a high initial investment in machinery and there is a specific set-up of operative environment, with prolonged operating time and a higher number of staff to achieve the goal of improved resection. In one series\u0026thinsp;~\u0026thinsp;28% of all pediatric tumor resections with iMRI received immediate further resection. This delivered GTR in \u0026gt;\u0026thinsp;95% of patients but added 2-4hours to the operation time.(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) In a specific analysis of iMRI in pLGG resection the use of iMRI increased the rate of intended GTR from 41\u0026ndash;71% compared to the cohort prior to introduction of iMRI and the remaining residual tumor volume was significantly lower.(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eA Cochrane review highlighted a lack of good quality evidence to support the use of any particular intraoperative imaging technology over another.(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) There was poor quality evidence regarding which technologies have the greatest efficacy and there was a lack of information about the impact on neurological function of more radical surgical resection. There are no ongoing or new trials evaluating iUS or iMRI that will influence treatment guidelines and policy.\u003c/p\u003e \u003cp\u003eThis article is intended to demonstrate and analyze the use and value of iUS or iMRI in the surgical treatment of pLGG patients based on accumulated experience from 4 large pediatric neuro-oncology centers across Europe and South Africa. All institutions are using iUS as routine with two centers having iMRI in routine use as well with sufficient previous experience in the field.(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003ePatients were included from the existing pediatric tumor registries in each hospital. The data were retrospectively collected and anonymized. All centers had institutional approval for retrospective data collection.\u003c/p\u003e \u003cp\u003eFor the iUS data, children aged 0\u0026ndash;18 years were included when histological diagnosis of pLGG was confirmed after surgery, iUS was used for either location and/or extent of resection of the tumor. Inclusion was done at Fondazione Policlinico Universitario A. Gemelli Roma (Italy) from 2017 till 2023, Steve Biko Academic Hospital Pretoria (South-Africa) from 2020 till 2024 and Universit\u0026auml;tsklinik Tuebingen (Germany) from 2014 till 2020. iUS was performed with MyLabTwice\u0026reg; microconvex probe (Esaote, Italy) in Roma; with Philips Epic Elite (Amsterdam, The Netherlands) probes L15-7io hockey stick and C8-5 curvilinear in Pretoria; and with Siemens Acuson (Siemens, Erlangen, Germany), BK5000 and BK Active, BK Medical, Copenhagen, Denmark) with linear 15 MHz Hockeystick probe and 10 MHz neurosurgery curvilinear probe in Tuebingen.\u003c/p\u003e \u003cp\u003eIn the Rome, Pretoria and Tuebingen iUS experience, iUS was methodically performed before opening the dura mater to assess the lesion site and its features. Brain parenchyma was insonated on standard planes repeatedly during different phases of tumor resection, and again once resection was completed and after dural closure, which could simplify the comparison with preoperative MRI. In addition, the Pretoria group\u0026rsquo;s imaging protocol also includes routinely performing ultrasound imaging of the optic nerve sheath at the beginning and at the end of the procedure. Concordance of iUS images with preoperative MRI is essential at this stage of surgery and may be time consuming, especially in early experience with iUS. In general, for frontal craniotomies coronal and sagittal planes are used, while coronal and axial planes are useful for temporal craniotomies. Usually, curved probes (5\u0026ndash;8 MHz) are used for large and deep lesions, although they might lack resolution. On the other hand, linear probes (6\u0026ndash;15 MHz) have higher spatial resolution and are used for small and superficial tumors.(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) The curved array probe with a 14mm ray of curvature allows for imaging in smaller craniotomy access and the ability to change the focus of the ultrasound beam provides the combined advantage of using linear and phased-array probes.\u003c/p\u003e \u003cp\u003eAdditionally, hybrid systems using preoperative MRI and iUS data allows real-time neuronavigated iUS, thanks to a magnetic coregistration of preoperative MRI and iUS, that could further aid the interpretation of iUS and orientation of the surgeon. In deep-seated lesions, iUS was also used to guide the surgical trajectory. It is important to re-scan the operative field by iUS during the course of resection with known and visible residual tumor to monitor progress of resection, appearance of artifacts and their different appearance to confirmed residual tumor. This improves the surgeons orientation, gives her/him a feeling for the residual disease and thus improves assessment at the end. After the macroscopic complete resection of the lesion according to the microsurgical view, or at the end of intended subtotal resection to functional limitations, US was repeated to assess the EOR on the same planes explored before resection and concordance with postoperative MRI was defined, as described elsewhere.(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eFor the iMRI data, children aged 0\u0026ndash;18 years were included when iMRI was used for resection control, histological diagnosis of LGG was confirmed after surgery, and preoperative intent of treatment was CR. Inclusion was done at Alder Hey Liverpool NHS trust (UK) from 2010 till 2023 and Universit\u0026auml;tsklinik Tuebingen (Germany) from 2014 till 2020. iMRI was performed by 3T-MRI in Liverpool (Philips Healthcare, Amsterdam, the Netherlands) and by 1.5T-MRI in Tuebingen (Espree, Siemens Medical Systems). Imaging included the brain tumor protocol with T1, T2, FLAIR, DWI and contrast-enhanced images.(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) The EOR on iMRI scan findings was based on evaluation performed in consensus by the radiologist and the operating neurosurgeon during iMRI acquisition.\u003c/p\u003e \u003cp\u003eVariables that were reviewed included patient demographics, location of the tumor (supratentorial or posterior fossa), EOR, pathological diagnosis, and follow-up of tumor where available.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eIntraoperative ultrasound\u003c/h2\u003e \u003cp\u003eThe iUS data of pLGG includes 111 operations in total (in 111 patients), 51 from Tuebingen, 35 from Rome and 25 from Pretoria. The details of these operations can be found in \u003cem\u003eTable\u0026nbsp;1\u003c/em\u003e. Patients included and analyzed contained all cases in a given time period, also those where subtotal resection due to functional limitations was the primary intention to treat. iUS was used for both purposes: to maximize the rate of CR in the group of patients where CR was the intention or to minimize the amount of residual tumor in the group where subtotal resection was the defined intention to treat. Two examples of peroperative imaging with iUS are demonstrated in Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cem\u003eTable\u0026nbsp;1. The combined data of resections of pLGG with use of iUS, gathered in three large pediatric neuro-oncology centres. The number of operations is divided into supratentorial (STT) or posterior fossa (PF) location. The extent of resection is divided into gross-total resection or incomplete resection, the number of operations as well as the percentage per centre are given. The median age in years is included.\u003c/em\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn the Tuebingen Cohort of 51 patients CR was the intent in 35 cases, STR due to obvious functional limitations in 16 patients, greatly depending on the anatomical region. Intraoperative neurophysiological monitoring was used if monitorable brain or brain stem function was involved at the site of surgery. In all 29 cases of supratentorial hemispheric and cerebellar hemispheric locations the intention to treat was CR. According to the reading of 3 months postoperative MRI, CR was reached in12/12 patients (supra-) and 15/17 patients (infratentorial). The remaining tissue volume in the 2 incomplete cerebellar cases was 0.1 ml and 0.4 ml respectively, therefore minimal. One was lost to follow-up, the other remained stable. In the 4th ventricle manifestations, CR was intended in 4 patients and only reached in 2 for functional reasons of ventricular floor infiltration. In all other locations (brainstem, supratentorial midline) we did define STR as goal of surgery, except for 2 cases in the thalamus. In one GTR was reached, in the other 6% of the tumor volume remained. The total number of patients in all locations with GTR was 30, follow-up was available for 29 patients. In two (6.9%) of these patients there was recurrence of disease. The US guided volume reduction in the 21 STR designed cases ranged from 22 to 98%, median 57% of initial tumor volume. Long-term follow-up regarding progression of residual disease after ultrasound guided resection was available for 18 patients with median follow-up 51months. In nine (50%) of these patients there was progression. These results are significantly different (Chi square test, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e \u003cp\u003eIn the Rome Cohort CR was the intent of surgery in 24 out of 28 supratentorial and in 5 out of 7 infratentorial tumors. Similar to the Tuebingen experience, intended STR for supratentorial tumors was performed to avoid obvious functional limitations (e.g. optic pathway glioma) or in case of large tumors involving the region of thalamus and basal ganglia. In the posterior cranial fossa, STR was performed in two cases of brainstem exophytic gliomas while CR was achieved in all cases of cerebellar hemispheric gliomas. This was similar in the Pretoria experience, where a combined structural and functional monitoring approach was used for all hemispheric and posterior fossa tumors, i.e combining iUS guidance with intra-operative neurophysiological monitoring (IONM) to achieve the goal of maximal safe resection. In Rome, no cases of recurrence were recorded after CR guided by iUS so far, with median follow-up of 36 months.\u003c/p\u003e \u003cp\u003eOverall, a total concordance of post-iUS to postoperative MRI was noted in Rome and Pretoria, although a detailed volumetric analysis of the residual tumor was not available for STR like for the Tuebingen cases. Interestingly, iUS was also able to detect intraoperative complications, such as a focal intraparenchymal hemorrhage secondary to brain collapse after the resection of a large intraventricular tumor.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eIntraoperative MRI\u003c/h3\u003e\n\u003cp\u003eThe iMRI data of pLGG with intent of CR includes 182 operations in total, 164 operations (in 150 patients) from Liverpool and 18 operations (in 18 patients) from Tuebingen. The details of these operations can be found in \u003cem\u003eTable\u0026nbsp;2.\u003c/em\u003e Two examples of peroperative imaging with iMRI are demonstrated in Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cem\u003eTable\u0026nbsp;2. The combined data of resections of pLGG with use of iMRI, gathered in two large pediatric neuro-oncology centres. The number of operations is divided into supratentorial (STT) or posterior fossa (PF) location. The extent of resection is divided into gross-total resection or incomplete resection, the number of operations as well as the percentage per centre are given. The median age in years is included.\u003c/em\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eLong-term follow-up regarding progression/recurrence of resection with iMRI was available for both Liverpool and Tuebingen. In the Liverpool data, CR was achieved at time of the first iMRI in 77 operations (47%), without need for further resection. In 73 operations (44.5%) we proceeded with second look surgery, which led to CR in 59 operations (80.8% of second look operations). In 5 operations, CR was achieved but the images of iMRI were not useful due to technical difficulties (CR was confirmed on postoperative MRI in the first 48 hours). In the total cohort of Liverpool, CR was achieved in 141 patients (86%) confirmed by MRI. Incomplete resection was mainly due to invasion of eloquent areas (more specific brainstem or cerebellopontine angle in the posterior fossa, supratentorial in cerebral hemisphere). Long-term follow-up was available in 144 operations (87.8%) with median follow-up of 46 months. In the CR group, there was recurrence of disease in 18 cases (14.2%). In the incomplete resection group, there was progression in 10 cases (58.8%), which is significantly more than the CR group (Chi square test, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e \u003cp\u003eIn the Tuebingen data, CR was achieved at time of the first iMRI in 4 operations (22.2%). In 14 operations (77.8%) we proceeded with second look surgery, which led to CR in 11 operations (78.6%). In the total cohort of Tuebingen, CR was achieved in 15 patients (83.3%) confirmed by MRI. Incomplete resection was mainly due to invasion of eloquent areas. Long-term follow-up was available in 17 operations (94.4%) with median follow-up of 61 months. In the CR group, there was recurrence of disease in 3 cases (21.4%). In the incomplete resection group, there was progression in one case (33.3%). These results are not significantly different (Chi square test, p 0.531). If we combine the long-term follow-up data of Liverpool and Tuebingen, in the group of CR there is recurrence of disease in 21 out of 141 cases (14.9%). In the incomplete resection group there is progression in 11 out of 20 cases (55%), which is significantly more than the CR group (Chi square test, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOptimizing the balance between extent of resection and preservation of neurological function remains the goal of brain tumor surgery. The value of structural monitoring during brain tumor surgery to contribute to this has been established in numerous studies.(\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) Our results present an overview of the use of perioperative imaging in all-day neurosurgery practice for pLGG, to optimize the extent of safe resection. There is a difference in the results of GTR in the iUS data from Tuebingen versus Roma/Pretoria. In the Tuebingen data, there were more posterior fossa medullar tumors included. Supratentorial there were multiple optic pathway gliomas included, which was different from the other centers, and there was no aim for GTR in these cases. For iMRI, there is a significant reduction in recurrence of pLGG when CR is confirmed on imaging in the Liverpool dataset. This was not significant in the Tuebingen data, but this was probably due to the relatively small sample size.\u003c/p\u003e \u003cp\u003eThe value of iUS for surgical-image guidance has enjoyed a tremendous upsurge in recent years. The real-time, portable, cost-effective benefits combined with the improved quality of imaging provided by modern probes has contributed to its increased utility in neurosurgery. First, it can be used to delineate and optimize the approach to the lesion, even before the dura is opened. Combining real-time iUS with neuronavigation, the last becoming less reliant during surgery due to resection and loss of cerebrospinal fluid, has further addressed some of the challenges limiting its widespread use. With the possibility of Doppler images in iUS, also blood vessels and flow are pictured which will help in the decision-making during resection.(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) iUS is considered an accessible first step to implement in a pediatric neurosurgery unit as an anatomical perioperative monitoring tool.\u003c/p\u003e \u003cp\u003eFurthermore, iUS may guide the surgical trajectory for deep-seated tumors and finally assess EOR. Assessment of EOR is affected by known limitations, that are largely described through literature. iUS features that define surgical margins as disease-free are unclear to date. Moreover, surgical artifacts may significantly hinder the assessment of surgical margins, in particular in large tumors with large cortical access and/or collapsed surgical cavity, as well as open ventricle. Several advances in the multiparametric application of ultrasound, which includes the use of ultrasound contrast agents (UCAs), ultrasound elastography, 3-dimensional navigated ultrasound and Doppler flow contribute significantly to improving the sensitivity of iUS for detecting residual tumor volume, though these modalities may not be available on many US systems and sufficient data on their use still does not exist in children. Despite these limitations, gaining experience with this technology may aid in defining surgical strategies or technical tricks to enhance the reliability of iUS.(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThus, iUS is a versatile surgical adjunct with an important role during the different stages of surgery, though the present study, as most of the studies published in the literature so far, focuses on the role of iUS in aiding to achieve CR.(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)The above named advantages provided by using iUS, along with its ease-of-use and repeatability, is the main difference when compared to iMR. iUS may therefore significantly contribute to steepen the learning curve in tumor surgery of young surgeons and we are convinced it helps to perfect the CR rates of experienced surgeons in all superficial tumor locations not deeper than 5-6cm from the brain surface.\u003c/p\u003e \u003cp\u003eiMRI has the advantages of higher resolution, less artefacts and being less dependent on the experience of the user. Especially in the deeper-seated locations, visualization with iMRI is better compared to iUS.(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) The high initial cost of equipment and the time it adds to the operation with an extensive staff make it not widespread available.(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) However, it has been proven that the use of iMRI reduces the need for early repeat surgery in pediatric brain tumors and that the perioperative images that confirm GTR pre-empt new postoperative MRI imaging.(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) Also in MRI, there is a continuous evolution in advanced imaging, which contributes to safely maximise the level of resection.(\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e)\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIntraoperative ultrasound and MRI have specific pros and cons, but both have been proven to improve the extent of resection in pediatric low-grade gliomas. For iMRI, since this is a static tool, it can easily be proven on sequential imaging with extent of resection and recurrence of disease as shown in our results. This is more difficult for iUS as it is a dynamic tool which is user dependent. Due to advances in image quality and cost- and time-efficiency, this is however the most accessible tool to date to aid in achieving the maximum possible tumor resection and should be combined whenever possible or meaningful with intraoperative neurophysiological monitoring.\u003c/p\u003e "},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eSD, CM, PF, LP ans MUS wrote and reviewed the main manuscript text. AN, CA, DH, DG, FB contributed to data collection. SD and DG did the analysis of the data. PF prepared figures 1 and 2, SD prepared figures 3 and 4.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData is available and anonymized at the participating centres.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBurnet NG, Jefferies SJ, Benson RJ, Hunt DP, Treasure FP (2005) Years of life lost (YLL) from cancer is an important measure of population burden \u0026mdash; and should be considered when allocating research funds. Br J Cancer 92(2):241\u0026ndash;245\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFangusaro J, Jones DT, Packer RJ, Gutmann DH, Milde T, Witt O et al (2024) Pediatric low-grade glioma: State-of-the-art and ongoing challenges. Neuro Oncol 26(1):25\u0026ndash;37\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCollins KL, Pollack IF (2020) Pediatric Low-Grade Gliomas. Cancers (Basel) 12(5):1152\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLouis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D et al (2021) The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol 23(8):1231\u0026ndash;1251\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBale TA, Rosenblum MK (2022) The 2021 WHO Classification of Tumors of the Central Nervous System: An update on pediatric low-grade gliomas and glioneuronal tumors. Brain Pathol. ;32(4)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBandopadhayay P, Bergthold G, London WB, Goumnerova LC, Morales La Madrid A, Marcus KJ et al (2014) Long-term outcome of 4,040 children diagnosed with pediatric low‐grade gliomas: An analysis of the Surveillance Epidemiology and End Results (SEER) database. Pediatr Blood Cancer 61(7):1173\u0026ndash;1179\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKelly PJ, Kall BA, Goerss S, Earnest F (1986) Computer-assisted stereotaxic laser resection of intra-axial brain neoplasms. J Neurosurg 64(3):427\u0026ndash;439\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eD\u0026rsquo;Amico RS, Kennedy BC, Bruce JN (2014) Neurosurgical oncology: advances in operative technologies and adjuncts. J Neurooncol 119(3):451\u0026ndash;463\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePadayachy LC, Fieggen G (2014) Intraoperative Ultrasound-Guidance in Neurosurgery. World Neurosurg 82(3\u0026ndash;4):e409\u0026ndash;e411\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrassanito P, Stifano V, Bianchi F, Tamburrini G, Massimi L (2023) Enhancing the Reliability of Intraoperative Ultrasound in Pediatric Space-Occupying Brain Lesions. Diagnostics 13(5):971\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSinghal A, Ross Hengel A, Steinbok P, Doug Cochrane D (2015) Intraoperative ultrasound in pediatric brain tumors: does the surgeon get it right? Child\u0026rsquo;s Nerv Syst 31(12):2353\u0026ndash;2357\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMattei L, Prada F, Legnani FG, Perin A, Olivi A, DiMeco F (2016) Neurosurgical tools to extend tumor resection in hemispheric low-grade gliomas: conventional and contrast enhanced ultrasonography. Child\u0026rsquo;s Nerv Syst 32(10):1907\u0026ndash;1914\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarai A, De Benedictis A, Calloni T, Onorini N, Patern\u0026ograve; G, Randi F et al (2021) Intraoperative Ultrasound-Assisted Extent of Resection Assessment in Pediatric Neurosurgical Oncology. Front Oncol 11:660805\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAvula S, Pettorini B, Abernethy L, Pizer B, Williams D, Mallucci C (2013) High field strength magnetic resonance imaging in paediatric brain tumour surgery\u0026mdash;its role in prevention of early repeat resections. Child\u0026rsquo;s Nerv Syst 29(10):1843\u0026ndash;1850\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoder C, Breitkopf M, Bisdas MS, Freitas S, da Dimostheni R (2016) Beneficial impact of high-field intraoperative magnetic resonance imaging on the efficacy of pediatric low-grade glioma surgery. Neurosurg Focus 40(3):E13\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJenkinson MD, Barone DG, Bryant A, Vale L, Bulbeck H, Lawrie TA et al (2018) Intraoperative imaging technology to maximise extent of resection for glioma. Cochrane Database Syst Reviews 2021:5\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAibar-Duran JA, Salgado-L\u0026oacute;pez L, Anka-Tugbiyele MO, Mirapeix RM, Gallardo Alca\u0026ntilde;iz A, Patino Alvarado JD et al (2024) Navigated intraoperative ultrasound in neuro-oncology: volumetric accuracy and correlation with high-field MRI. J Neurosurg. ;1\u0026ndash;10\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCraig E, Connolly DJA, Griffiths PD, Raghavan A, Lee V, Batty R (2012) MRI protocols for imaging paediatric brain tumours. Clin Radiol 67(9):829\u0026ndash;832\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAvula S, Peet A, Morana G, Morgan P, Warmuth-Metz M, Jaspan T (2021) European Society for Paediatric Oncology (SIOPE) MRI guidelines for imaging patients with central nervous system tumours. Child\u0026rsquo;s Nerv Syst 37(8):2497\u0026ndash;2508\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNuwer MR, Dawson EG, Carlson LG, Kanim LEA, Sherman JE (1995) Somatosensory evoked potential spinal cord monitoring reduces neurologic deficits after scoliosis surgery: results of a large multicenter survey. Electroencephalogr Clin Neurophysiology/Evoked Potentials Sect 96(1):6\u0026ndash;11\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYou H, Qiao H (2021) Intraoperative Neuromonitoring During Resection of Gliomas Involving Eloquent Areas. Front Neurol. ;12\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRadtke RA, Erwin CW, Wilkins RH (1989) Intraoperative brainstem auditory evoked potentials. Neurology 39(2):187\u0026ndash;187\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBastos DCDA, Juvekar P, Tie Y, Jowkar N, Pieper S, Wells WM et al (2021) Challenges and Opportunities of Intraoperative 3D Ultrasound With Neuronavigation in Relation to Intraoperative MRI. Front Oncol. ;11\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShi J, Zhang Y, Yao B, Sun P, Hao Y, Piao H et al (2021) Application of Multiparametric Intraoperative Ultrasound in Glioma Surgery. Biomed Res Int 2021:1\u0026ndash;18\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGiussani C, Trezza A, Ricciuti V, Di Cristofori A, Held A, Isella V et al (2022) Intraoperative MRI versus intraoperative ultrasound in pediatric brain tumor surgery: is expensive better than cheap? A review of the literature. Child\u0026rsquo;s Nerv Syst 38(8):1445\u0026ndash;1454\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoiyadi AV (2016) Intraoperative Ultrasound Technology in Neuro-Oncology Practice\u0026mdash;Current Role and Future Applications. World Neurosurg 93:81\u0026ndash;93\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMunkvold BKR, Jakola AS, Reinertsen I, Sagberg LM, Unsg\u0026aring;rd G, Solheim O (2018) The Diagnostic Properties of Intraoperative Ultrasound in Glioma Surgery and Factors Associated with Gross Total Tumor Resection. World Neurosurg 115:e129\u0026ndash;e136\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbernethy LJ, Avula S, Hughes GM, Wright EJ, Mallucci CL (2012) Intra-operative 3-T MRI for paediatric brain tumours: challenges and perspectives. Pediatr Radiol 42(2):147\u0026ndash;157\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAvula S, Jaspan T, Pizer B, Pettorini B, Garlick D, Hennigan D et al (2021) Comparison of intraoperative and post-operative 3-T MRI performed at 24\u0026ndash;72 h following brain tumour resection in children. Neuroradiology 63(8):1367\u0026ndash;1376\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMato D, Velasquez C, G\u0026oacute;mez E, Marco de Lucas E, Martino J (2021) Predicting the Extent of Resection in Low-Grade Glioma by Using Intratumoral Tractography to Detect Eloquent Fascicles Within the Tumor. Neurosurgery 88(2):E190\u0026ndash;202\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"childs-nervous-system","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cnsy","sideBox":"Learn more about [Child's Nervous System](http://link.springer.com/journal/381)","snPcode":"381","submissionUrl":"https://submission.nature.com/new-submission/381/3","title":"Child's Nervous System","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Pediatric low-grade glioma, extent of resection, intraoperative ultrasound, intraoperative MRI","lastPublishedDoi":"10.21203/rs.3.rs-4644683/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4644683/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003ePediatric low-grade gliomas (pLGG) are the most common brain tumors in children and achieving complete resection (CR) is the most important prognostic factor. There are multiple intraoperative tools to optimise the extent of resection (EOR). This article investigates and discusses the role of intraoperative ultrasound (iUS) and intraoperative magnetic resonance imaging (iMRI) in the treatment of pLGG.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe tumor registries at Tuebingen, Rome and Pretoria were searched for pLGG with the use of iUS and data on EOR. The tumor registries at Liverpool and Tuebingen were searched for pLGG with the use of iMRI where preoperative CR was the surgical intent. Different iUS and iMRI machines were used in the 4 centers.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eWe included 111 operations which used iUS and 182 operations using iMRI. Both modalities facilitated intended CR in hemispheric supra- and infratentorial location in almost all cases. In more deep seated tumor location like supratentorial midline tumors, iMRI has advantages over iUS to visualize residual tumor. Functional limitations limiting CR arising from eloquent involved or neighboring brain tissue apply to both modalities in the same way. In the long-term follow-up, both iUS and iMRI show that achieving a complete resection on intraoperative imaging significantly lowers recurrence of disease (Chi-square test, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eiUS and iMRI have specific pros and cons, but both have been proven to improve achieving CR in pLGG. Due to advances in image quality, cost- and time-efficiency, and efforts to improve the user interface, iUS has emerged as the most accessible surgical adjunct to date to aid and guide tumor resection. Since the EOR has the most important effect on long term outcome and disease control of pLGG in most locations, we strongly recommend taking all possible efforts to use iUS in any surgery, independent of intended resection extent, and iMRI if locally available.\u003c/p\u003e","manuscriptTitle":"Role of intraoperative ultrasound and MRI to aid grade of resection of pediatric low-grade gliomas. Accumulated experience from 4 centers","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-19 20:32:20","doi":"10.21203/rs.3.rs-4644683/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2024-07-01T16:23:28+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-29T05:55:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"72315781151469101839882395702743771801","date":"2024-06-28T21:34:30+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-28T17:00:20+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-27T05:00:55+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-27T05:00:28+00:00","index":"","fulltext":""},{"type":"submitted","content":"Child's Nervous System","date":"2024-06-26T19:46:58+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"childs-nervous-system","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cnsy","sideBox":"Learn more about [Child's Nervous System](http://link.springer.com/journal/381)","snPcode":"381","submissionUrl":"https://submission.nature.com/new-submission/381/3","title":"Child's Nervous System","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"6c313c25-89fd-48d8-8066-cda955ff5d48","owner":[],"postedDate":"July 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-07-19T20:57:54+00:00","versionOfRecord":{"articleIdentity":"rs-4644683","link":"https://doi.org/10.1007/s00381-024-06532-3","journal":{"identity":"childs-nervous-system","isVorOnly":false,"title":"Child's Nervous System"},"publishedOn":"2024-07-16 20:57:54","publishedOnDateReadable":"July 16th, 2024"},"versionCreatedAt":"2024-07-19 20:32:20","video":"","vorDoi":"10.1007/s00381-024-06532-3","vorDoiUrl":"https://doi.org/10.1007/s00381-024-06532-3","workflowStages":[]},"version":"v1","identity":"rs-4644683","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4644683","identity":"rs-4644683","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}