Are all questions about the safety of MRI contrast agent answered?

by Hans-Klaus Goischke (hkem.goischke@t-online.de)

Kromrey ML, Liedtke KR, Ittermann T, et al. (2017) Intravenous injection of gadobutrol in an epidemiological study group did not lead to a difference in relative signal intensities of certain brain structures after 5 years. Eur Radiol. 2017 Feb;27(2):772-777.

Dear Editor,

Deposition of Gadolinium (Gd) in various organs and tissues from contrast MRIs has been consistently reported in animals and in humans. Although this is associated with all agents, the extent is much less with the macrocyclic Gd based-contrast agent (mGBCA). The conclusions from the study of Kromrey et al. [1] described in the key points are undifferentiated and one-sided – the complexity of Gd deposits is not observed. The publication is not suitable, did can limit Gd body burden. They write in the “Key Points “: “Macrocyclic contrast agents in a proven dosage are safe”. Can this be determined with only a single Magnetic Resonance Imaging (MRI) after 5 years? This message suggests security without observing the clinical symptoms. Without observing the symptoms post injection, there is insufficient evidence for this statement. The clinical significance of Gd tissue deposition is crucial. The role of the mGBCAs in possible clinical and biological effects of Gd accumulation is therefore not determined. Is gadobutrol representative of all mGBCAs?

Another key issue is whether the MRI technique used was sensitive enough? Kanda reported: The detectability of high signal intensity in the dentate nucleus differs between spin-echo T1WI and T1 FLAIR. The dentate nucleus is hyperintense on spin-echo T1WI, but not on T1 FLAIR. The different detectabilities of hyperintense dentate nuclei on various sequences may have influenced their results [2] Tedeschi et al. [3] performed MR scans at 3 Tesla, while the Kromrey et al authors 1.5 Tesla. MR examinations (Intracranial Gd- deposition after contrast-enhanced MR Imaging) were performed with 3 Tesla instruments and others by McDonald et al [4]. The focus after administration of GBCA must be in patients with frequent applications, particularly in multiple sclerosis. This is especially true for vulnerable patient groups, who will have longer exposure to the deposited Gd. High signal intensity of both the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images correlates with the number of previous GBCA administration. In multiple sclerosis, previous Gd administrations correlate with dentate nuclei T1 relaxometry [3]. MR relaxometry can quantitatively assess Gd accumulation in dentate nuclei. The first report regarding gadolinium deposition in patients came in 2004 [5]. They described the presence of Gd in resected femoral head specimens.

Newer reports have emerged regarding the accumulation of Gd in various tissues, including brain, bone and skin. Gd deposited in the bone can persist long term. Murata et al [6] collected tissue samples from 9 decedents undergoing autopsy who had single agent contrast-enhanced magnetic resonance imaging (MRI) exposure with macrocyclic and linear GBCA (5 Decedents gadoteridol, 2 received gadobutrol, 1 gadobenate and 1 gadotexate). The result: Gd deposition in normal brain and bone tissue occurs with macrocyclic and linear GBCA. Bone levels measured 23 times higher than brain levels. White et al [7] and Darrah et al [8] who demonstrated that Gd is sequestered in bone matrix after intravenous administration. It remains possible that bone matrix may rapidly take up small fraction of intravenously administered GBCA and act as a reservoir, slowly releasing Gd with subsequent uptake in other tissues. Stojanov et al reported: Gd deposition my occur within the human brain after multiple Gd contrast administration, including from the mGBCA-gadobutrol [9]. In addition, Kanda et al doubt the results of the study [10].

An extremely vulnerable group of patients are children and adolescence with multiple sclerosis (MS). The monitoring of therapy using MRI with doses of GBCA can lead to high cumulative Gd concentrations throughout the patient`s life. Brain development begins during fetal life and continues throughout adolescence. During this critical period of development (“maturational changes in the human brain”), the brain is particularly vulnerable to toxin exposure. Roberts et al demonstrated in pediatric patients that the number of prior GBCA doses significantly correlated with progressive T1-weighted hyperintensity in the dentate nucleus [11]. Caution is called for when monitoring MS therapy with GBCAs in young women with MS who may become pregnant. Gd deposition after repeated contrast-enhanced MR imaging can result in Gd deposits in the bones. Pregnancy can lead to mobilization of Gd come from the bone. Released Gd can then cause of health issues in the mother and fetus, because Gd penetrates through the placenta. GBCA administration has only been approved under the assumptions that the potential substantial benefits outweigh any know risks. The detection of disease activity (MS), defined as new / enlarging T2 lesions on brain MR imaging, has been proposed as a biomarker in MS and is also possible in principle without GBCA. The technical implementation and evaluation of MR imaging without the use of a GBCA requires an increased amount of time, but is possible. Cabezas et al demonstrate the improved automatic detection of new T2 lesions in multiple sclerosis using deformation fields. The automatic detection could reduce user interaction and inter- and intraobserver variability [12]. Semelka et al. informs us that Gd in humans can causa health issues – a family of disorders. He describes at least 4 major Gd disorders. First: Nephrogenic Systemic Fibrosis, secondly: Severe acute adverse event, thirdly: Gd storage condition (GSC), fourthly: Gd deposition disease (GDD) (a new entity that represents symptomatic deposition of Gd in individuals with normal renal function) [13]. Patients develop persistent symptoms that arise within hours to 2 month following the administration of GBCAs. The results of a patient advocacy group-initiated survey of 17 patients show the onset of a group of symptoms within a month of their last MRI [14]. These symptoms range from neurological, musculoskeletal, to dermal, including pain (reported by 100% of patients surveyed), muscle symptoms reported by 88%, and ocular symptoms (reported by 76%). More than 50% of those surveyed reported having symptoms in each of the other symptoms categories (e.g., dermal, cognitive)[14,15]. 15 of the 17 patients surveyed had urinary gadolinium levels above expected levels for patients with normal renal function [14]. Semelka et al. report typical clinical features included persistent headache, and bone and joint pain. Patients often complain of clouded mentation, that many describe as brain fog. Patients often experience subcutaneus soft tissue thickening that clinically appears somewhat spongy or rubbery [13]. Gathings et al. describe Gd associated plaques as a new, distinct clinical entity [16]. It is important to include the clinical symptoms in the assessment of GBCA safety. Is valid still “from symptom to the diagnosis”. Presently there is no aftercare of patients following GBCA administration. If Kromrey et al had made clinical assessments of each patient during years 1 to 4, a statement could be made about the safety of the single GBCA the studied. A solution to this dilemma: Quantitative MRI for analysis of active multiple sclerosis lesions without Gd-based contrast agent? [17-23]. Prospective studies incorporating measurement of serum and urine Gd3+ and clinical symptoms can help correlate thes Gd3+ body burden with MRI T1-weighted intensity data (13,15). The distinction between side effects caused by diagnostics and side effects of drug therapies is essential for optimal adherence and persistence to the disease therapy. It would be desirable if the new findings and clinical symptoms described would result in a longer-term follow-up. Changes are needed; we cannot carry on as if nothing has happened.

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