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Histogram of the number of macrocyclic ionic MR contrast agent administrations in the study population. https://doi.org/10.1371/journal.pone.0183916.g003
Source publication
Purpose
To determine whether multiple repeated administrations of gadolinium-based macrocyclic ionic MR contrast agent (MICA) are associated with intracranial gadolinium deposition and identify the predisposing factors for deposition in various clinical situations.
Materials and methods
In this institutional review board-approved retrospective stu...
Citations
... This hyperintensity with gadobutrol administration has also been observed in patients with brain tumours, with a statistically significant dose-dependent enhancement seen in the dentate nucleus (Bjørnerud et al. 2017). Multiple, repeated administrations of macrocyclic agents did not result in hyperintensities with normal renal function, but was seen in those with renal impairment in the dentate nucleus (Lee et al. 2017). This finding of hyperintensity associated with macrocyclic usage, is not always found, and this discrepancy is not well understood and may be as a result of different scanners, field strength or imaging protocols. ...
Gadolinium-based contrast agents (GBCAs) have transformed magnetic resonance imaging (MRI) by facilitating the use of contrast-enhanced MRI to allow vital clinical diagnosis in a plethora of disease that would otherwise remain undetected. Although over 500 million doses have been administered worldwide, scientific research has documented the retention of gadolinium in tissues, long after exposure, and the discovery of a GBCA-associated disease termed nephrogenic systemic fibrosis, found in patients with impaired renal function. An understanding of the pharmacokinetics in humans and animals alike are pivotal to the understanding of the distribution and excretion of gadolinium and GBCAs, and ultimately their potential retention. This has been well studied in humans and more so in animals, and recently there has been a particular focus on potential toxicities associated with multiple GBCA administration. The purpose of this review is to highlight what is currently known in the literature regarding the pharmacokinetics of gadolinium in humans and animals, and any toxicity associated with GBCA use.
... Yes [14][15][16]18,[104][105][106] Yes [14,102,[107][108][109][110][111][112] Yes [18,105]/No [113] No [114] Yes [115]/No [16,[116][117][118][119] No [106,117,120] Yes [121]/No [104,107,112,118,122] No b a Based on the EMA recommendation [123,124]. b Low risk by design [57,58,[125][126][127][128], no T 1 hyperintensity in animal models [56,126,129]. ...
The extracellular class of gadolinium-based contrast agents (GBCAs) is an essential tool for clinical diagnosis and disease management. In order to better understand the issues associated with GBCA administration and gadolinium retention and deposition in the human brain, the chemical properties of GBCAs such as relative thermodynamic and kinetic stabilities and their likelihood of forming gadolinium deposits in vivo will be reviewed. The chemical form of gadolinium causing the hyperintensity is an open question. On the basis of estimates of total gadolinium concentration present, it is highly unlikely that the intact chelate is causing the T1 hyperintensities observed in the human brain. Although it is possible that there is a water-soluble form of gadolinium that has high relaxitvity present, our experience indicates that the insoluble gadolinium-based agents/salts could have high relaxivities on the surface of the solid due to higher water access. This review assesses the safety of GBCAs from a chemical point of view based on their thermodynamic and kinetic properties, discusses how these properties influence in vivo behavior, and highlights some clinical implications regarding the development of future imaging agents.
... Since that initial description, multiple studies in adults [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] and children [18][19][20][21][22][23][24][25][26] have confirmed the dose-dependent association. However, nearly all of these studies have shown this association to be present after the administration of linear GBCM but not macrocyclic GBCM [2,4,9,11,16,19,[25][26][27][28][29][30][31][32][33][34][35]. Subsequent tissue-based studies have confirmed that the increased T1-W signal is associated with gadolinium deposition [36][37][38][39]. ...
... These studies have evaluated for increased T1-W signal in the dentate nucleus and the globus pallidus, even though gadolinium deposition has been reported in other structures after administration of linear GBCM. Finally, only a small number of the studies of macrocyclic agents has evaluated MRI pulse sequence, scanner (vendor and field strength) or individual factors that might influence detection of increased T1-W signal in the brain [2,19,25,31,32,34,35]. ...
... The prior study showed that 3-T MRI scanners were more sensitive for detecting T1-W SI ratio changes than 1.5-T magnets after repeated gadopentetate dimeglumine administration. Prior studies have not found a significant difference in identifying the changes in SI ratios based on MRI scanner field strength [2,5,31,34,35]. In this study, the effect was striking after gadoterate meglumine administration, with 10/26 (38%) SI ratios showing a significant effect based on a P-value of less than 0.002. In the gadopentetate dimeglumine arm, only 1 showed an effect with a P-value less than 0.002. ...
Background
Repeated administrations of linear gadolinium-based contrast media (GBCM) are associated with T1-weighted (T1-W) signal intensity change in brain structures.
Objective
The purpose of this study was to compare different brain structures in children after unconfounded, repeated administrations of either a macrocyclic or linear GBCM.
Materials and methods
We performed a retrospective cohort study, identifying subjects with ≥5 unconfounded administrations of gadoterate meglumine. We matched subjects with repeated administrations of gadopentetate dimeglumine to the gadoterate meglumine arm based on the number of unconfounded GBCM administrations. Two reviewers drew regions of interest on 27 structures in and around the brain. We recorded demographic, modality and study parameters and evaluated them to determine whether they were associated with T1-W signal intensity (SI) changes. Linear mixed effects models evaluated the relationships between the number of GBCM doses and T1-W SI ratio. Finally, we identified differences in the rate of T1-W SI ratio change among individuals using a linear mixed effects model with random slope.
Results
We included a total of 52 patients (age range at first MRI: 6.0 months to 17.1 years), 26 in each arm. We detected a significant change in the T1-W SI ratio with repeated administrations of GBCM in one location in the gadoterate meglumine arm and in four locations in the gadopentetate dimeglumine arm. Patient gender and age were not associated with T1-W SI change. Modality vendor, imaging sequence and field strength were variably associated with a systematic difference in the ability to detect a T1-W SI change. Finally, linear mixed effects model with random slope showed that there were individual differences in the slope of SI change at various structures among individuals for both arms. This effect was present in more brain structures in the gadopentetate dimeglumine arm (14 vs. 8).
Conclusion
There is a significant change in the T1-W SI ratio over time in multiple brain structures after repeated gadopentetate dimeglumine administrations. This effect was only seen in one ratio after repeated administrations of gadoterate meglumine. There are individual differences in the rate of change of SI ratios over time after repeated administration of gadopentetate dimeglumine and gadoterate meglumine, suggesting that individual differences are present.
... If MRI is not available or cannot be performed, computed tomography (CT) or head ultrasound (in neonates or infants when fontanelles are open) may be used, although these frequently will not detect all abnormalities revealed by MRI [23,24]. (Category 1) J o u r n a l P r e -p r o o f Recently, gadolinium deposition in the brain has drawn attention [25], although newer macrocyclic gadolinium agents lower the risk of depositions compared to older linear gadolinium agents [26,27] and the long-term clinical implications are unknown [25,28]. While gadolinium can be used to better demonstrate SEGAs, in light of the need for repeated scans during childhood and potential side effects of contrast agents, combined with non-contrast imaging sequences generally sufficient for screening for SEGA, we recommend avoiding until there is a growing lesion or clinical suspicion of SEGA. ...
Background
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations.
Methods
Chairs and working group co-chairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference July 25-26 in Dallas, TX, USA. Prior to the meeting, working group co-chairs worked with group members via email and telephone to a) review TSC literature since the 2013 publication, b) confirm or amend prior recommendations, and c) provide new recommendations as required.
Results
Only two changes were made to clinical diagnostic criteria reported in 2013: “multiple cortical tubers and/or radial migration lines” replaced the more general term “cortical dysplasias,” and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for EEG abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals.
Conclusions
Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families.
... For example, stable macrocyclic agents such as gadoterate meglumine and gadoteridol were not associated with significantly higher relative signal intensities in the globus pallidus or dentate nuclei when compared with less stable linear agents such as gadodiamide or gadopentetate dimeglumine [81]. Additional studies have also shown that even after giving multiple serial injections (20-52) of a macrocyclic agent, no abnormally increased signal intensity in the brain was seen on the unenhanced T1-weighted images [82,83]. Numerous studies have confirmed these findings in the pediatric population as well [84][85][86]. ...
Gadolinium-based contrast agents (GBCAs) have been used to improve image quality of MRI examinations for decades and have an excellent overall safety record. However, there are well-documented risks associated with GBCAs and our understanding and management of these risks continue to evolve. The purpose of this review is to discuss the safety of GBCAs used in MRI in adult and pediatric populations. We focus particular attention on acute adverse reactions, nephrogenic systemic fibrosis and gadolinium deposition. We also discuss the non-GBCA MRI contrast agent ferumoxytol, which is increasing in use and has its own risk profile. Finally, we identify special populations at higher risk of harm from GBCA administration.
... It is the case of gadobutrol formulated as Gadovist 1.0 mmol/ml or 0.5 mmol/ml, reported in the past [11]. For instance, Lee and colleagues [152] reported perfusion performed with Dotarem 0.5 M (gadoterate meglumine). The authors report a standard single dose of 13 ml and double dose for perfusion studies: It follows that the dose is not proportional to body weight as it is in most studies and protocols. ...
This article reports known and emerging adverse health effects associated with the administration of gadolinium-based contrast agents. It focuses on the issue of the incomplete excretion of these drugs leading to the deposition of gadolinium in the tissues of the patients. The evidence of deposition is reviewed. The analysis presents gaps in our knowledge but also suggests neglected or still poorly considered parameters to possibly explain discrepancies among studies (e.g. off-label use; rate of administration; gadolinium concentration in the pharmaceutical formulation, cumulative metal toxicity). The article also presents a critical assessment of some aspects reported in the literature as well as future needs. Potential biases in the investigation and evaluation of the health/clinical implications associated with gadolinium deposition are pointed out. The analysis emphasizes that the vast majority of the clinical studies conducted up to date on gadolinium-based contrast agents were designed to assess acute toxicity and diagnostic efficacy of the agents, not to identify long-term health effects.
... Our data show that MRI scanners with a 3-T field strength are not more sensitive for detecting T1-W signal hyperintensity related to GBCM administration than scanners with a 1.5-T field strength. These data are in line with previous reports by Lee et al. [32], Cao et al. [5] and Adin et al. [2]. ...
Background
Gadolinium deposition occurs following repeated administration of gadolinium-based contrast media. However, few studies have evaluated factors that lead to increased detection of deposition or the individual differences among patients.
Objective
To measure the effect of repeated dosages of gadopentetate dimeglumine on pediatric brains and to determine the factors that influence signal intensity changes.
Materials and methods
A retrospective study evaluated magnetic resonance imaging (MRI) in patients <18 years of age who received >5 doses of gadopentetate dimeglumine. Regions of interest were placed in 30 locations in the brain on axial precontrast T1 images. Signal intensity ratios were evaluated throughout the brain. The effect of increasing gadopentetate dimeglumine exposure on signal intensity ratios was assessed using linear mixed models adjusted for gender, age, imaging sequence type (fast spin echo or gradient echo), MRI manufacturer (General Electric, Philips or Siemens), and field strength (1.5 tesla [T] or 3 T). Finally, the variance of the random slope in the linear mixed models was tested to determine if there were differences in the rate of signal intensity ratio change among individuals.
Results
Fifty patients (M:F=25:25; mean age at first imaging: 6.4 years) with a mean of 21.5 gadopentetate dimeglumine administrations (range: 6–86) were included. There were significant increases in T1 signal in the globus pallidus, dentate nucleus and pulvinar with an increasing number of contrast administrations. Patient gender, age, and MRI field strength were not associated with changing signal intensity ratios. However, MRI sequence type and vendor significantly impacted some measured signal intensity ratios. Finally, significant differences in the slopes of the ratios were present among patients for multiple locations.
Conclusion
Repeated administration of gadopentetate dimeglumine is associated with T1 hyperintense signal in the dentate nucleus, globus pallidus and pulvinar. Detection is significantly affected by MRI sequence type and scanner vendor. Even when accounting for these differences, there are individual differences in the slope of signal intensity change suggesting a patient-level effect influences gadolinium deposition.
... Many studies have suggested that elevated brain MRI SI, particularly in the dentate nucleus, is associated with lifetime Gd dose [12][13][14][15]. Several pediatric studies have examined the effect of repeated GBCA administration on brain MRI SI in children with conflicting results [13,[15][16][17][18][19][20][21][22][23][24]. Some studies show that increased brain MRI SI is influenced by the chemical stability and amount of the specific GBCA used, while others show that SI is influenced by patients' ages, underlying diagnoses, and the number of Gd studies they undergo. ...
Background
Contrast enhanced magnetic resonance imaging (MRI) is an important tool for the assessment of extracardiac vasculature and myocardial viability. Gadolinium (Gd) brain deposition after contrast enhanced MRI has recently been described and resulted in a warning issued by the United States Food and Drug Administration. However, the prevalence of brain deposition in children and adults with congenital heart disease (CHD) undergoing cardiovascular magnetic resonance (CMR) is unclear. We hypothesized that Gd exposure as part of one or more CMRs would lead to a low rate of brain deposition in pediatric and adult CHD patients.
Methods
We queried our institutional electronic health record for all pediatric and adult CHD patients who underwent contrast enhanced CMR from 2005 to 2018 and had a subsequent brain MRI. Cases were age- and gender-matched to controls who were never exposed to Gd and underwent brain MRIs. The total number of contrast enhanced MRIs, type of Gd, and total Gd dose were determined. Brain MRIs were reviewed by a neuroradiologist for evidence of Gd deposition using qualitative and quantitative assessment. Quantitative assessment was performed using the dentate nucleus to pons signal intensity ratio (dp-SIR) on T1 weighted imaging. Continuous variables were analyzed using Mann–Whitney U and Spearman rank correlation tests. Normal SIR was defined as the 95% CI of the control population dp-SIR.
Results
Sixty-two cases and 62 controls were identified. The most contrast enhanced MRIs in a single patient was five and the largest lifetime dose of Gd that any patient received was 0.75 mmol/kg. There was no significant difference in the mean dp-SIR of cases and controls (p = 0.11). The dp-SIR was not correlated with either the lifetime dose of Gd (r s = 0.21, p = 0.11) or the lifetime number of contrast enhanced studies (r s = 0.21, p = 0.11). Two cases and 2 controls had dp-SIRs above the upper bound of the 95% confidence interval for the control group. One case had qualitative imaging-based evidence of Gd deposition in the brain but had a dp-SIR within the normal range.
Conclusion
In our cohort of pediatric and adult CHD patients undergoing contrast enhanced CMR, there was a low incidence of qualitative and no significant quantitative imaging-based evidence of Gd brain deposition.
... In a study on rats, Lohrke et al. [23] reported some 15-time higher brain tissue concentration of linear GBCAs compared to macrocyclic GBCAs and reported that Gd's chelating stability played an important role in this observation. Lee et al. [24], on the other hand, reported no intensity increase in DNs and GPs of patients that undergone at least 2 MRI examinations with macrocyclic-ionic GBCA. Renz et al. [25] compared linear-ionic GBCA (gadopentetate dimeglumine) and macrocyclic-nonionic GBCA (gadobutrol) among pediatric patients who underwent more than three examinations with GBCA; they reported hyperintensity in both GP and DN in both groups. ...
Aim: Gadoterate meglumine is a macrocyclic-ionic gadolinium-based contrast agent (GBCA) which is using in the magnetic resonance imaging (MRI). This study aims to determine the relationship between the signal intensity (SI) increase in the dentate nucleus (DN), pons (P), globus pallidus (GP), thalamus (T) and use gadoterate meglumine by repeated brain MRI in lung cancer patients.Methods: The study was designed as a retrospective cohort study. The mean SIs of the DN, P, GP, and T and the cerebrospinal fluid (CSF) were measured in the unenhanced T1-weighted (T1w) images of the first and last MRIs of patients who underwent at least three brain MRI examinations with gadoterate meglumine. DN, P, GP, T SIs were divided by values obtained from CSF to standardize the SI measurements. The DN, P, GP, T SIs and DN/CSF, P/CSF, GP/CSF, T/CSF ratios were compared the first and the last MRI examinations.Results: Our study revealed significant increases in DN, P, GP, and T SIs (P<0.001, P<0.001, P<0.001 and P=0.024,respectively). DN/CSF, P/CSF, GP/CSF, and T/CSF ratios were also significantly increased (P<0.001, P<0.001, P<0.001 and P=0.022, respectively). The number of examinations had a moderately strong positive correlation with in the DN/CSF ratio and a strong positive correlation with in P/CSF ratio (P<0.001 and P<0.001, respectively). There was a weak positive correlation between MRI intervals and in P/CSF ratio (P=0.037).Conclusion: Our study suggested an increase in the first and the last MRI in DN, P, GP and T SIs related to the number and intervals of repeated examinations of a brain MRI with gadoterate meglumine among patients with lung cancer.
... Many studies have investigated the association between T1 hyperintensities in the globus pallidus and dentate nucleus and multiple administrations of linear GBCAs (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). In retrospective human studies that included patients with multiple linear GBCAs, T1 signal changes in the dentate nucleus and/or globus pallidus were consistently associated with multiple administrations of nonspecific extracellular linear GBCAs, such as gadodiamide (11,12,17,22) and gadopentetate (11,13,19,23,26 Imaging S.p.A.]), which are more stable, have found that macrocyclic GBCAs were not associated with significant signal intensity changes in the globus pallidus and dentate nucleus in the brain (52,(80)(81)(82)(83). Studies comparing linear (gadopentetate) and macrocyclic (gadoteridol or gadoterate meglumine) agents have reconfirmed that the signal intensity change is significantly and exclusively related to the use of linear agents (14-16, 20, 84, 85). ...
Korean J Radiol. 2019;20:e15. English.
ABSTRACT
Gadolinium-based contrast agents (GBCAs) are commonly used for enhancement in MR imaging and have long been considered safe when administered at recommended doses. However, since the report that nephrogenic systemic fibrosis is linked to the use of GBCAs in subjects with severe renal diseases, accumulating evidence has suggested that GBCAs are not cleared entirely from our bodies; some GBCAs are deposited in our tissues, including the brain. GBCA deposition in the brain is mostly linked to the specific chelate structure of the GBCA: linear GBCAs were responsible for brain deposition in almost all reported studies. This review aimed to summarize the current knowledge about GBCA brain deposition and discuss its clinical implications.
