Objective: This study compares the incidence of new-onset symptoms within 24 hours after enhanced magnetic resonance imaging (eMRI) with intravenous administration of gadodiamide or gadoterate meglumine compared with a control group undergoing unenhanced MRI (uMRI). Materials and Methods: A prospective cohort study (n = 1088 patients) was designed to assess the incidence of symptoms within 24 hours after administration of gadodiamide or gadoterate meglumine. The participants underwent a structured questionnaire by phone call before and 24 hours after the MRI scan to check for symptoms that were not present before the scan. The questionnaire included a list of active questions aimed to test the prevalence of symptoms that have been proposed in the debated definition of gadolinium deposition disease (GDD) and that we recorded in this study as GDD-like. In particular, the following symptoms and signs were tested: central torso pain, arm or leg pain, bone pain, headache, skin redness (any site of the body), fatigue, and mental confusion.Fisher exact test was used to test differences between groups with significance threshold set at P < 0.05. Results: Within the 24 hours after the MRI scan, 8.3% of patients reported at least one new-onset symptom in the uMRI group versus 17.4% in the gadodiamide eMRI versus 17.8% in the gadoterate meglumine eMRI group. The difference between the eMRI and the uMRI group was statistically significant (P < 0.001 for gadodiamide and P < 0.001 for gadoterate meglumine). There was not a different incidence of symptoms between the gadodiamide and the gadoterate meglumine eMRI groups. For gadodiamide, fatigue (P < 0.05) and dizziness (P < 0.05) were symptoms significantly more frequent than uMRI group; for gadoterate meglumine, fatigue (P < 0.01), mental confusion (P < 0.01), and diarrhea (P < 0.01) were significantly more frequent than uMRI group. Conclusions: We found that the onset of new symptoms within 24 hours after exposure to gadolinium-based contrast agent was more frequent than after uMRI. Among GDD-like symptoms, fatigue and mental confusion were the most frequent symptoms reported after eMRI. The other GDD-like symptoms were not overreported after eMRI versus uMRI. Thus, these results are questioning the term GDD.

The aim of this study was to assess the presence of detectable changes of skin thickness on clinical brain magnetic resonance imaging (MRI) scans in patients with MS, history of multiple gadolinium-based contrast agents (GBCAs) administrations, and evidence of gadolinium deposition in the brain. Materials and Methods: In this observational cross-sectional study, 71 patients with MS who underwent conventional brain MRI with an imaging protocol including enhanced 3D volumetric interpolated breath-hold examination (VIBE) T1-weighted with fat saturation were assessed. Patients with bilateral isointense dentate nucleus on unenhanced T1-weighted images were assigned to group A (controls without MRI evidence of gadolinium deposition), and patients with visually hyperintense dentate nuclei were assigned to group B. Qualitative and quantitative assessment of the skin thickness were performed. Results: Group A included 27 patients (median age, 33 years [IQR,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46]; 20 women), and group B included 44 patients (median age, 42 years [IQR,[35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53]; 29 women). Qualitative and quantitative assessment of the skin revealed significant differences between group A and group B. The average skin-to-scalp thickness ratios was significantly higher in group B than in group A (mean ± standard deviation = 0.52 ± 0.02 in group B vs 0.41 ± 0.02 in group A, P < 0.0001) and showed a positive correlation with the total number of enhanced MRI scans (r = 0.39; 95% confidence interval, 0.17-0.57, P < 0.01). Conclusions: Brain MRI detects increased skin thickness of the scalp in patients with MS and dentate nucleus high signal intensity on unenhanced T1-weighted images and shows positive association with previous exposures to linear GBCAs rather than macrocyclic GBCAs.

Objectives The aim of this study was to summarize the current preclinical and clinical evidence on the association between exposure to gadolinium (Gd) compounds and skin toxicity in a setting similar to clinical practice. Materials and Methods A search of MEDLINE and PubMed references from January 2000 to December 2022 was performed using keywords related to gadolinium deposition and its effects on the skin, such as “gadolinium,” “gadolinium-based contrast agents,” “skin,” “deposition,” and “toxicity.” In addition, cross-referencing was added when appropriate. For preclinical in vitro studies, we included all the studies that analyzed the response of human dermal fibroblasts to exposure to various gadolinium compounds. For preclinical animal studies and clinical studies, we included only those that analyzed animals or patients with preserved renal function (estimated glomerular filtration rate >30 mL/min/1.73 m2), using a dosage of gadolinium-based contrast agents (GBCAs) similar to that commonly applied (0.1 mmol/kg). Results Forty studies were selected. Preclinical findings suggest that Gd compounds can produce profibrotic responses in the skin in vitro, through the activation and proliferation of dermal fibroblasts and promoting their myofibroblast differentiation. Gadolinium influences the process of collagen production and the collagen content of skin, by increasing the levels of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1. Preclinical animal studies show that Gd can deposit in the skin with higher concentrations when linear GBCAs are applied. However, these deposits decrease over time and are not associated with obvious macroscopic or histological modifications. The clinical relevance of GBCAs in inducing small fiber neuropathy remains to be determined. Clinical studies show that Gd is detectable in the skin and hair of subjects with normal renal function in higher concentrations after intravenous administration of linear compared with macrocyclic GBCA. However, these deposits decrease over time and are not associated with cutaneous or histological modifications. Also, subclinical dermal involvement related to linear GBCA exposure may be detectable on brain MRI. There is no conclusive evidence to support a causal relationship between GBCA administration at the clinical dose and cutaneous manifestations in patients with normal renal function. Conclusions Gadolinium can produce profibrotic responses in the skin, especially acting on fibroblasts, as shown by preclinical in vitro studies. Gadolinium deposits are detectable in the skin even in subjects with normal renal function with higher concentrations when linear GBCAs are used, as confirmed by both preclinical animal and human studies. There is no proof to date of a cause-effect relationship between GBCA administration at clinical doses and cutaneous consequences in patients with normal renal function. Multiple factors, yet to be determined, should be considered for sporadic patients with normal renal function who develop clinical skin manifestations temporally related to GBCA administration.

No abstract