Safety of Intrathecal Gadolinium-based Contrast Agents and Benefit versus Risk

HomeRadiologyVol. 299, No. 1 PreviousNext CommunicationsFree AccessLetters to the EditorSafety of Intrathecal Gadolinium-based Contrast Agents and Benefit versus RiskGeir Ringstad*, Per Kristian Eide†,‡ Geir Ringstad*, Per Kristian Eide†,‡ Author AffiliationsDepartment of Radiology and Nuclear Medicine* andDepartment of Neurosurgery,† Oslo University Hospital, Rikshospitalet, Pb 4950 Nydalen, N-0424 Oslo, NorwayInstitute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway‡e-mail: [email protected]Geir Ringstad*Per Kristian Eide†,‡ Published Online:Feb 16 2021https://doi.org/10.1148/radiol.2021203351MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In Editor:We thank Dr Patel and colleagues (1) for a timely meta-analysis of adverse events associated with intrathecal administration of gadolinium-based contrast agents (GBCAs), published in the October 2020 issue of Radiology. Their article was submitted shortly before the publication of our prospective safety study of 100 patients intrathecally administered 0.5 mmol of gadobutrol (2). In this, we conclude that the procedure is safe, adding to the finding of no observed serious adverse events at doses of 1 mmol or less in the meta-analysis.We would like to mention that the reported small margin of safety (range, 1.0–2.0 mmol) should in practice be considered larger. In our experience, 0.5 mmol is always sufficient to enrich the entire cerebrospinal fluid (CSF) compartments in the spinal canal and at the skull base. Among the 1036 patients incorporated in the meta-analysis, a dose of 1.0 mmol had been given to fewer than 50 patients, indicating this dosage is uncommon. In a follow-up to our prospective study with 49 new patients, we presented preliminary data showing that 0.25 mmol is sufficient to maintain CSF enhancement at diagnostic levels (published in Neuroradiology [3]), improving the safety profile significantly. We also advocate the use of a syringe no larger than 1 mL to prevent accidental injection of GBCA in potentially neurotoxic doses and at the same time allow for a more precise dosage.An editorial (4) emphasized that controlled studies of off-label applications are a mainstay of clinical advances, and that benefit-to-risk ratio of intrathecal GBCA always must be taken into consideration. As we now move on using gadobutrol intrathecally in doses previously shown to be safe in a controlled study setting, we will also continue to explore new prospects inherent with the methodology to diagnose other neurologic diseases than CSF leaks. Recent discoveries of the ability to bypass the blood-brain barrier with intrathecal gadobutrol, thereby enhancing the entire brain extravascular compartment and moreover the potential ability to serve as a surrogate marker for extravascular clearance of neurotoxic proteins (5,6), may call for a later reassessment of the benefit-to-risk ratio.Disclosures of Conflicts of Interest: G.R. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: disclosed payment for lectures and speakers fees from Bayer. Other relationships: disclosed no relevant relationships. P.K.E. disclosed no relevant relationships.References1. Patel M, Atyani A, Salameh JP, McInnes M, Chakraborty S. Safety of Intrathecal Administration of Gadolinium-based Contrast Agents: A Systematic Review and Meta-Analysis. Radiology 2020. 10.1148/radiol.2020191373. Published online July 28, 2020. Google Scholar2. Edeklev CS, Halvorsen M, Løvland G, et al. Intrathecal Use of Gadobutrol for Glymphatic MR Imaging: Prospective Safety Study of 100 Patients. AJNR Am J Neuroradiol 2019;40(8):1257–1264. Crossref, Medline, Google Scholar3. Halvorsen M, Edeklev CS, Fraser-Green J, Løvland G, Vatnehol SAS, Gjertsen Ø, Nedregaard B, Sletteberg R, Ringstad G, Eide PK. Off-label intrathecal use of gadobutrol: safety study and comparison of administration protocols. Neuroradiology. 2021 Jan;63(1):51–61 Crossref, Medline, Google Scholar4. Kanal E. A Reality Check on Intrathecal Gadolinium-based Contrast Agents. Radiology 2020. 10.1148/radiol.2020202819. Published online July 28, 2020. Google Scholar5. Ringstad G, Valnes LM, Dale AM, et al. Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI Insight 2018;3(13):e121537. Crossref, Medline, Google Scholar6. Ringstad G, Eide PK. Cerebrospinal fluid tracer efflux to parasagittal dura in humans. Nat Commun 2020;11(1):354. Crossref, Medline, Google ScholarReferences1. Patel M, Atyani A, Salameh JP, McInnes M, Chakraborty S. Safety of Intrathecal Administration of Gadolinium-based Contrast Agents: A Systematic Review and Meta-Analysis. Radiology 2020. 10.1148/radiol.2020191373. Published online July 28, 2020. Link, Google Scholar2. Edeklev CS, Halvorsen M, Løvland G, et al. Intrathecal Use of Gadobutrol for Glymphatic MR Imaging: Prospective Safety Study of 100 Patients. AJNR Am J Neuroradiol 2019;40(8):1257–1264. Crossref, Medline, Google ScholarReferences1. Patel M, Atyani A, Salameh JP, McInnes M, Chakraborty S. Safety of Intrathecal Administration of Gadolinium-based Contrast Agents: A Systematic Review and Meta-Analysis. Radiology 2020. 10.1148/radiol.2020191373. Published online July 28, 2020. Google Scholar2. Edeklev CS, Halvorsen M, Løvland G, et al. Intrathecal Use of Gadobutrol for Glymphatic MR Imaging: Prospective Safety Study of 100 Patients. AJNR Am J Neuroradiol 2019;40(8):1257–1264. Crossref, Medline, Google Scholar3. Halvorsen M, Edeklev CS, Fraser-Green J, Løvland G, Vatnehol SAS, Gjertsen Ø, Nedregaard B, Sletteberg R, Ringstad G, Eide PK. Off-label intrathecal use of gadobutrol: safety study and comparison of administration protocols. Neuroradiology. 2021 Jan;63(1):51–61 Crossref, Medline, Google Scholar4. Kanal E. A Reality Check on Intrathecal Gadolinium-based Contrast Agents. Radiology 2020. 10.1148/radiol.2020202819. Published online July 28, 2020. Google Scholar5. Ringstad G, Valnes LM, Dale AM, et al. Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI Insight 2018;3(13):e121537. Crossref, Medline, Google Scholar6. Ringstad G, Eide PK. Cerebrospinal fluid tracer efflux to parasagittal dura in humans. Nat Commun 2020;11(1):354. Crossref, Medline, Google ScholarResponseMihilkumar Patel, Almohannad Atyani, Jean-Paul Salameh, Matthew D. F. McInnes, Santanu Chakraborty Mihilkumar Patel, Almohannad Atyani, Jean-Paul Salameh, Matthew D. F. McInnes, Santanu Chakraborty Author AffiliationsDepartment of Medical Imaging, Division of Neuroradiology, University of Ottawa, Ottawa Hospital Research Institute, 1053 Carling Ave, Ottawa, ON, Canada K1Y 4E9e-mail: [email protected]We thank Drs Ringstad and Eide for their valuable input regarding our meta-analysis (1). In their letter, they discussed their recent study, which concluded that intrathecal GBCA use was safe and effective at a dose of 0.5 mmol (2). It is reassuring that their result from a large sample size prospective study is consistent with our conclusions of no observed adverse events at GBCA doses less than 1.0 mmol. Furthermore, they report preliminary evidence in support of the use of GBCAs at 0.25 mmol for adequate CSF enhancement while minimizing the risk of adverse events.We provide anecdotal local evidence regarding similar success to that reported by Drs Ringstad and Eide with low-dose GBCAs. We found that the use of 0.25 mmol of gadobutrol in a 1-mL syringe mixed with iodinated contrast agent provided adequate diagnostic enhancement of CSF compartments and allowed us to detect CSF leaks that were undetectable by using CT cisternography. The benefits of the use of lower doses of GBCAs are clear in that they likely reduce the risk of adverse events. However, we were unable to advocate for the use of lower GBCA dose on the basis of the studies that were included in the meta-analysis at the time.In our study, we found a small margin of safety between 1.0 and 2.0 mmol. This was a result of the lack of data regarding the safety of intrathecal GBCA use between 1.0 and 2.0 mmol in the literature. Furthermore, 1.0 mmol was the highest dose at which there were no reported serious adverse events. Unfortunately, we could not further assess specific dose-response relationships at lower doses because the majority of the studies did not assess adverse events as a primary outcome. Although it is likely that doses significantly less than 1.0 mmol provide adequate diagnostic enhancement, we were unable to analyze this further and as a result cannot explicitly recommend a larger margin of safety at this time. However, the preliminary data presented by Drs Ringstad and Eide are promising in addressing the current gap in knowledge regarding the effective use of low-dose GBCAs in CSF enhancement while comparing their safety risk. Disclosures of Conflicts of Interest: M.P. disclosed no relevant relationships. A.A. disclosed no relevant relationships. J.P.S. disclosed no relevant relationships. M.D.F.M. disclosed no relevant relationships. S.C. disclosed no relevant relationships.References1. Patel M, Atyani A, Salameh JP, McInnes M, Chakraborty S. Safety of Intrathecal Administration of Gadolinium-based Contrast Agents: A Systematic Review and Meta-Analysis. Radiology 2020. 10.1148/radiol.2020191373. Published online July 28, 2020. Link, Google Scholar2. Edeklev CS, Halvorsen M, Løvland G, et al. Intrathecal Use of Gadobutrol for Glymphatic MR Imaging: Prospective Safety Study of 100 Patients. AJNR Am J Neuroradiol 2019;40(8):1257–1264. 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