Statement on the Effects of Gadolinium
Reports such as that published in the leading German newspaper “Die Welt“ on 08.02.2016 and in other important newspapers have been appearing in the media for some weeks. What is the truth about the reported deposition of extracellular gadolinium (GAD) in the brain? The US Food and Drug Administration (FDA) commented on reports and in a Drug Safety Communication of July 2015 stated that specific extracellular GAD contrast media can be deposited in particular areas of the brain such as the pons and the thalamus if they are used repeatedly (more than four times), for example in magnetic resonance imaging (MRI) examinations in patients with chronic diseases such as multiple sclerosis and tumor growth. Comparison of the signal intensity of these structures in cranial MR images taken in follow-up examinations showed an increase.
Signal intensity increase in follow-up cranial MRI
The announcement of this information in the press led to colleagues in nuclear medicine warning of a great danger of GAD deposition in the brain when used in cardiac MRI. As a result newspaper reports called for unnecessary MRI examinations with GAD administration, in particular cardiac MRI, to be no longer performed and for a return to less dangerous examinations such as single photon emission computed tomography (with X-ray exposure of up to 20 mSv) in combination with echocardiograpy (for example in the Hamburger Abendblatt of 10.02.2016).
A review of the literature shows that there are currently approximately 18 experimental and clinical publications relating to this topic. These publications do describe the phenomenon of an increase in signal intensity in cranial MRI; however, there are no reports of accompanying pathological features or measurable changes. Thus the FDA has not changed the information leaflets that accompany the different contrast media. Further, several highly regarded research groups are currently working on the topic to identify possible serious side effects of potential cerebral GAD deposits.
As we MR cardiologists use GAD contrast media in almost all our patients to identify tissue ischemia, vitality, fibrosis and inflammation, it is important to consider the implications of the existing information for our clinical practice.
So what do we know from the publications so far?
- Up until now it is entirely unclear in what form the GAD is found in brain tissue. Only a few reports1-3 have found GAD to be present in any form in the relevant areas of the brain, apparently most of it in the endothelium3. It should be borne in mind, however, that the unchanged GAD chelate complex cannot cross the blood‑brain barrier due to its molecular structure and size3a.
- It seems that renal function does not influence this process of deposition, since the phenomenon of hyperintensity was also observed in patients with normal renal function who received GAD contrast medium for repeated MRI examinations4.
- Apparently the patient’s disease does play a role, since MS patients showed greater enhancement than tumor patients in the work published so far by Radbruch and colleagues2.
- The molecular structure of the GAD contrast medium also seems to be relevant. Linear, non-ionic contrast media (according to the ESUR Guidelines 9.0 these are the GAD contrast media with high risk for the nephrogenic systemic fibrosis [NSF] described) seem to lead to stronger enhancement in the brain than the modern macrocyclic GAD chelates (according to the ESUR Guidelines 9.0 the GAD contrast media with low NSF risk). Nevertheless, after administration of the so-called NSF low risk GAD contrast media, minimal deposits in the brain were still found5..
- Further, the enhancement phenomena were shown in all observed brain areas3.
- It is interesting that the phenomenon was not observed in all patients who repeatedly received GAD contrast medium. Although Kanda et al. showed a linear correlation between signal intensity increase and the frequency of GAD administration, there are also patients who show no increase at all in signal intensity after up to 12 applications1. It is problematical that the type and amount of GAD contrast medium are not always exactly recorded and that the studies are often based on very mixed patient collectives.
What are the implications for clinicians of this data?
- The extracellular gadolinium contrast media allowed in Germany are very well tolerated and even pseudoallergic reactions occur in less than 0.2% of cases8.
- Nevertheless, we as responsible MRI clinicians should always carefully consider the specific clinical question and its meaningfulness before we decide to administer GAD contrast medium.
- In view of the inhomogenous retrospective data concerning GAD contrast medium application it is important to meticulously document the amount, kind and dose of the GAD contrast medium given.
- Since the situation is at present unclear our patients should, for the time being, receive macrocyclic GAD contrast medium in the minimal possible dosage for a diagnostic examination. These media seem to lead to an increase in the signal intensity but to a lesser extent than the high risk GAD contrast media.
To conclude, at the moment there are no nationally or internationally binding guidelines or recommendations on how GAD contrast media should be applied from now on. The German X-Ray Society (Deutsche Röntgengesellschaft) has only commented that since 2015 a group of experts has been observing further developments in this area.
Henning Steen & Sebastian Kelle
References may be obtained from the authors
