Retention of Gadolinium-Based Contrast Agents in Multiple Sclerosis: Retrospective Analysis of an 18-Year Longitudinal Study

Forslin, Yngve; Shams, Sara; Hashim, Farouk; Aspelin, Peter; Bergendal, Gösta; Martola, Juha; Fredrikson, Sten; Wiberg, Maria Kristoffersen; Granberg, Tobias

doi:10.3174/ajnr.a5211

Cited by 54 publications

(46 citation statements)

References 37 publications

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“…The study by Welk et al involving 99,739 patients with one or more Gd-enhanced MRI and 146,818 control patients with only non-enhanced MRIs did not find a significant association with parkinsonism [20]. A very recent retrospective cohort study involving nearly 20 years of longitudinal data in 23 multiple sclerosis patients and 23 healthy age-and sex-matched controls found a possible association between Gd exposure and cognitive impairment (verbal fluency) [21]. However, it should be noted that these findings need to be interpreted with caution since retrospective studies are highly susceptible to 'confounding by indication'.…”

Section: Methodological Limitations Of Current Studiesmentioning

confidence: 99%

“…Thus far, two studies aimed to assess the possible influence of gadolinium accumulation and clinical symptoms [20,21]. The study by Welk et al involving 99,739 patients with one or more Gd-enhanced MRI and 146,818 control patients with only non-enhanced MRIs did not find a significant association with parkinsonism [20].…”

Section: Methodological Limitations Of Current Studiesmentioning

confidence: 99%

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Gadolinium retention after administration of contrast agents based on linear chelators and the recommendations of the European Medicines Agency

2017

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The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) earlier this year recommended to suspend some marketing authorisations for Gadolinium Containing Contrast Agents (GCCAs) based on linear chelators due to the potential risk of gadolinium retention in the human body. These recommendations have recently been re-evaluated by EMA's Committee for Medicinal Products for Human Use (CHMP), and confirmed the final opinion of the European Medicines Agency. This editorial provides an overview of the available GCCAs and summarises the recent evidence of gadolinium retention. Moreover, a critical appraisal of the strengths and limitations of the scientific evidence currently available on gadolinium retention is given. Key points • EMA recommended suspension of some EU marketing authorisations of four linear GCCAs. • Brain MRI findings indicating gadolinium retention have been confirmed by mass spectrometry.• Current scientific evidence for gadolinium retention has several methodological limitations.• No clear clinical evidence exists indicating that gadolinium retention causes neurotoxicity.• Long-term safety of GCCAs, however, remains unclear.

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Section: Methodological Limitations Of Current Studiesmentioning

confidence: 99%

Section: Methodological Limitations Of Current Studiesmentioning

confidence: 99%

Gadolinium retention after administration of contrast agents based on linear chelators and the recommendations of the European Medicines Agency

2017

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“…Investigation of the effect of gadolinium deposition in the brain and cerebellum of patients with neurological diseases is challenged by the disease itself and local treatments such as surgery and radiation therapy …”

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confidence: 99%

“…23 Investigation of the effect of gadolinium deposition in the brain and cerebellum of patients with neurological diseases is challenged by the disease itself and local treatments such as surgery and radiation therapy. 24,25 Crohn's disease is a chronic inflammatory bowel disease characterized by gut inflammation relapses, recurrent episodes of intestinal symptoms, and poor quality of life. 26 Patients with symptoms of Crohn's disease routinely undergo MR enterography and/or MR of the pelvis and, in most cases, receive intravenous injections of GBCAs.…”

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confidence: 99%

Absence of dentate nucleus resting‐state functional connectivity changes in nonneurological patients with gadolinium‐related hyperintensity on T₁‐weighted images

Mallio

Piervincenzi

Gianolio

et al. 2019

Magnetic Resonance Imaging

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Background The dentate nuclei of the cerebellum are the areas where gadolinium predominantly accumulates. It is not yet known whether gadolinium deposition affects brain functions. Purpose/Hypothesis To assess whether gadolinium‐dependent high signal intensity of the cerebellum on T1‐weighted images of nonneurological adult patients with Crohn's disease is associated with modifications of resting‐state functional connectivity (RSFC) of the cerebellum and dentate nucleus. Study Type Observational, cross‐sectional. Population Fifteen patients affected by Crohn's disease were compared with 16 healthy age‐ and gender‐matched control subjects. All participants underwent neurological, neurocognitive‐psychological assessment, and blood sampling. Field Strength/Sequence 1.5‐T magnet blood oxygenation level‐dependent (BOLD) functional MRI. Assessment High signal intensity on T1‐weighted images, cerebellum functional connectivity, neurocognitive performance, and blood circulating gadolinium levels. Statistical Tests An unpaired two‐sample t‐test (age and sex were nuisance variables) was used to investigate between‐group differences in cerebellar and dentate nucleus functional connectivity. Z‐statistical images were set using clusters determined by Z > 2.3 and a familywise error (FWE)‐corrected cluster significance threshold of P = 0.05. Results Dentate nuclei RSFC was not different (P = n.s.) between patients with gadolinium‐dependent high signal intensity on T1‐weighted images and controls. Pre‐ and postcentral gyrus bilaterally and the right supplementary motor cortex showed a decrease of RSFC with the cerebellum hemispheres (P < 0.05 FWE‐corrected) and was related to disease duration but not to gadodiamide cumulative doses (P = n.s.). Data Conclusion Crohn's disease patients with gadolinium‐dependent hyperintense dentate nuclei on unenhanced T1‐weighted images do not show dentate nucleus RSFC changes. Level of Evidence: 2 Technical Efficacy Stage: 5 J. Magn. Reson. Imaging 2019;50:445–455.

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“…The clinical significance of these findings has not yet been elucidated; however, a cautious approach has been suggested. [89][90][91] For MS patients, repeated MR exams with Gd-based contrast agent are routine for follow-up and treatment monitoring. The contrast agent is necessary for detection of active lesions with damaged BBB and contrast leakage, which can impact the treatment regime.…”

Section: Paper IImentioning

confidence: 99%

Clinical Applications of Synthetic MRI of the Brain

Blystad¹

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Magnetic Resonance Imaging (MRI) has a high soft-tissue contrast with a high sensitivity for detecting pathological changes in the brain. Conventional MRI is a time-consuming method with multiple scans that relies on the visual assessment of the neuroradiologist. Synthetic MRI uses one scan to produce conventional images, but also quantitative maps based on relaxometry, that can be used to quantitatively analyse tissue properties and pathological changes. The studies presented here apply the use of synthetic MRI of the brain in different clinical settings. In the first study, synthetic MR images were compared to conventional MR images in 22 patients. The contrast, the contrast-to-noise ratio, and the diagnostic quality were assessed. Image quality was perceived to be inferior in the synthetic images, but synthetic images agreed with the clinical diagnoses to the same extent as the conventional images. Patients with early multiple sclerosis were analysed in the second study. In patients with multiple sclerosis, contrast-enhancing white matter lesions are a sign of active disease and can indicate a need for a change in therapy. Gadolinium-based contrast agents are used to detect active lesions, but concern has been raised regarding the long-term effects of repeated use of gadolinium. In this study, relaxometry was used to evaluate whether pre-contrast injection tissue-relaxation rates and proton density can identify active lesions without gadolinium. The findings suggest that active lesions often have relaxation times and proton density that differ from non-enhancing lesions, but with some overlap. This makes it difficult to replace gadolinium-based contrast agent injection with synthetic MRI in the monitoring of MS patients. Malignant gliomas are primary brain tumours with contrast enhancement due to a defective blood-brain barrier. However, they also grow in an infiltrative, diffuse manner, making it difficult to clearly delineate them from surrounding normal brain tissue in the diagnostic workup, at surgery, and during follow-up. The contrast-enhancing part of the tumour is easily visualised, but not the diffuse infiltration. In studies three and four, synthetic MRI was used to analyse the peritumoral area of malignant gliomas, and revealed quantitative findings regarding peritumoral relaxation changes and non-visible contrast enhancement suggestive of non-visible infiltrative tumour growth. In conclusion, synthetic MRI provides quantitative information about the brain tissue and this could improve the diagnosis and treatment for patients

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Retention of Gadolinium-Based Contrast Agents in Multiple Sclerosis: Retrospective Analysis of an 18-Year Longitudinal Study

Cited by 54 publications

References 37 publications

Gadolinium retention after administration of contrast agents based on linear chelators and the recommendations of the European Medicines Agency

Gadolinium retention after administration of contrast agents based on linear chelators and the recommendations of the European Medicines Agency

Absence of dentate nucleus resting‐state functional connectivity changes in nonneurological patients with gadolinium‐related hyperintensity on T₁‐weighted images

Clinical Applications of Synthetic MRI of the Brain

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Retention of Gadolinium-Based Contrast Agents in Multiple Sclerosis: Retrospective Analysis of an 18-Year Longitudinal Study

Cited by 54 publications

References 37 publications

Gadolinium retention after administration of contrast agents based on linear chelators and the recommendations of the European Medicines Agency

Gadolinium retention after administration of contrast agents based on linear chelators and the recommendations of the European Medicines Agency

Absence of dentate nucleus resting‐state functional connectivity changes in nonneurological patients with gadolinium‐related hyperintensity on T1‐weighted images

Clinical Applications of Synthetic MRI of the Brain

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Product

Resources

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Absence of dentate nucleus resting‐state functional connectivity changes in nonneurological patients with gadolinium‐related hyperintensity on T₁‐weighted images