MRI Contrast Agents: Intracranial Gadolinium Retention
Intracranial Gadolinium Retention and High Signal Intensity in Globus Pallidus and Dentate Nucleus on Unenhanced T1-weighted MR Images: A Review of the Literature*
[*Special thanks to Alberto Spinazzi, M.D., Global Medical and Regulatory Affairs, Bracco Diagnostics, Inc.]
Some patients exposed to multiple administrations of certain gadolinium-based contrast agents (GBCAs) may exhibit progressively increased signal intensity (SI) in the globus pallidus (GP) and the dentate nucleus (DN) on unenhanced T1-weighted brain images (1-10). This monograph provides a cumulative review of relevant literature relating to this abnormal imaging finding and to the potential deposition of gadolinium in brain tissues.
Studies described in this document were published in the peer-reviewed literature. The first report on abnormal T1 shortening seen in the GP and DN was available online in December 2013 and published in March 2014 (1). A systematic and comprehensive online search was performed using the following databanks: Embase, Biosis, Medline, and Derwent Drug File for publications printed from December 2013 through September 2015. The search was conducted using the search terms: “gadolinium” or “gadolinium-based contrast agent” or “gadolinium deposition” or “gadolinium retention” or “dentate nucleus” or “globus pallidus” or “brain”. The results were limited to human data and excluded duplicates, review articles, case reports, editorials, conference abstracts or papers, news, and commentaries. Due to the limited precision of the index terms used by the online databases, a screening was performed by experienced medical reviewers to include citations that were pertinent.
Certain patients exposed to multiple administrations of GBCAs may exhibit progressively increased SI in the GP and the DN on unenhanced T1-weighted brain images (1-10). Abnormal T1 shortening has been observed after serial application of certain GBCAs and not others. Kanda, et al. (3) reported that, while a significant increase in SI in the DN and GP occurred after multiple doses of the linear GBCA Magnevist (active ingredient: gadopentetate dimeglumine), this abnormal finding did not occur after multiple doses of the macrocyclic GBCA ProHance (active ingredient: gadoteridol). Radbruch, et al. (6) showed that SI increase in the DN and GP on T1-weighted images is caused by serial application of Magnevist but not by the macrocyclic GBCA Dotarem (active ingredient: gadoterate meglumine). Ramalho, et al. (7) reported that patients who received the linear GBCA Omniscan (active ingredient: gadodiamide) showed a significant increase in signal intensity in the DN and GP compared to other brain areas (thalamus, TH, and middle cerebral peduncles, MCP). Conversely, those who received the linear GBCA MultiHance did not show a significant increase in SI in the DN or GP. These results were not confirmed by Weberling, et al. (10) who instead reported an increase in SI in the DN after serial injections of MultiHance (active ingredient: gadobenate dimeglumine). Differences in patient population and study methodology may explain the different results from these two studies, especially less rigorous control of previous exposure to other GBCAs in the study by Weberling, et al. (10). T1 hyperintensity in the GP and DN following repeated administrations of Omniscan were observed by Errante, et al. (2), Quattrocchi, et al. (4) and McDonald, et al. (5), while Stojanov, et al. (8) reported a significant increase in SI in the DN and GP in patients with multiple sclerosis following multiple exposure to the macrocyclic GBCA Gadavist (active ingredient: gadobutrol).
In summary, abnormal T1 shortening was observed following repeated prior administration of the linear agents Omniscan and Magnevist, and of an agent with a macrocyclic ligand, Gadavist. Inconsistent results were reported for the linear GBCA MultiHance. Increased SI in the GP or DN has not been reported following serial exposure to the macrocyclic GBCAs ProHance and Dotarem, or the linear agents OptiMARK (active ingredient: gadoversetamide), Eovist (active ingredient: gadoxetate disodium), and Ablavar (active ingredient: gadofoveset trisodium).
Importantly, none of the authors of the clinical investigations published so far has ever reported any symptoms in their patients that would relate to damage to the GP, the DN, or other brain structures (1-10).
Evidence of Gadolinium Deposition in Brain Tissues
Two investigations have associated abnormal T1 shortening in the GP and DN with deposition of gadolinium in brain autopsy specimens. Kanda, et al. (11) conducted an investigation using brain tissues obtained at autopsy in five subjects who were exposed to multiple administrations of GBCAs (GBCA group) and five subjects with no history of GBCA administration (non-GBCA group). The GBCAs involved were Magnevist, Omniscan, and ProHance. By using inductively coupled plasma mass spectroscopy to determine the presence and concentration of gadolinium in the brain tissues, Kanda, et al. (11) showed that, following repeated GBCA administration, gadolinium accumulates in the brain, and that the concentration of gadolinium was higher in the DN and GP than in other regions. Gadolinium was detected in all specimens in the GBCA group. Of note, gadolinium was also present in some specimens in the non-GBCA group. However, the gadolinium concentration was significantly higher in the GBCA group.
A study by McDonald, et al. (5) reported that, in patients with hyperintensity in the DN and GP on unenhanced T1-weighted MR images following exposure to multiple doses of Omniscan, the majority of gadolinium deposits were in the endothelial walls, with a smaller fraction in the brain interstitium. Importantly, no signs of neuronal damage were observed at microscopy of the involved brain tissues.
The findings of McDonald, et al. (5) are consistent with those previously reported by Sanyal, et al. (12) who performed an analysis of tissues obtained during autopsy of a patient with verified advanced nephrogenic systemic fibrosis (NSF). Using light microscopy and scanning electron microscopy/energy-dispersive X-ray spectroscopy, Sanyal, et al. (12) found gadolinium deposits in the perivascular glial cells in the cerebellum but not in the pons, thalamus or corpus striatum.
Gadolinium Form in Brain Tissues
Free gadolinium ions are not expected to survive in a physiological environment. Studies performed in human plasma have shown that the gadolinium ions released in transmetallation reactions distribute into a number of species, mostly phosphates, or complexes with small (e.g. citrate) and large (e.g. albumin) biomolecules (13, 14). Neither Kanda, et al. (11) nor McDonald, et al. (5) determined the form in which gadolinium is retained in brain tissues, while Sanyal, et al. (12) could only find insoluble gadolinium phosphates. Gadolinium phosphates have very low solubility and precipitate into particles that have little or no effect on water proton relaxation rate, that is, on SI on T1-weighted images (13, 14). Therefore, the enhanced SI observed in the DN and GP on T1-weighted images is not expected to be dependent on gadolinium phosphate complexes but is likely due either to intact molecules of the administered GBCA or to the formation of soluble gadolinium complexes. Other metals (e.g., manganese) could also contribute to the overall effect on SI. In none of the three studies aimed at determining the presence of gadolinium in the brain was investigation made of the presence and concentration of other metals or factors that could contribute to SI increase in the DN and GP on T1-weighted images (5, 11, 12).
Factors That May Influence the Deposition of Gadolinium in Brain Tissues
The central nervous system (CNS) is sealed from the blood milieu by the blood-brain barrier (BBB), localized at the level of the endothelial cells within CNS microvessels, and the blood-cerebrospinal fluid (CSF) barrier (BCSFB), established by choroid plexus epithelial cells (15). The lack of permeability of the BBB and the absence of intra-parenchymal enhancement on post-contrast scans suggest that it is an unlikely pathway for gadolinium penetration under normal conditions (16, 17). There is a list of pathologies affecting the CNS that involve an element of BBB dysfunction, including multiple sclerosis, hypoxia and ischemia, edema, Parkinson's disease, dementia or Alzheimer's disease, epilepsy, primary or secondary tumors, acute brain injuries, lysosomal storage diseases, and diabetes (15, 17). If there is BBB disruption, for example in patients with diabetes or focal lesions, SI increases following administration of GBCAs are usually observed in several areas of the brain. A study by Starr, et al. (18) in patients with type II diabetes revealed SI increases in several brain areas after injection of a GBCA with the greatest increase observed in the basal ganglia. The SI increase seen in diabetic subjects was consistent with previous theoretical models and similar to that observed in single lesions in multiple sclerosis. Importantly, there were no signs of gadolinium retention or accumulation, at least after a single exposure to a GBCA: after 30 minutes, the SI time profile for diabetic subjects was similar to that of the healthy controls in all brain areas, with statistical linear decline closer to a real time exponential decline and consistent with first order kinetics (18). Whether and how gadolinium, in any form (intact GBCA molecule or other compounds), may progressively accumulate in the DN and GP in patients who have, or have had, BBB disruption is unknown. Sanyal, et al. (12) found gadolinium in the perivascular glial cells in the cerebellum of a patient who had developed NSF but no gadolinium deposits were found in the brain interstitium, that is, there was no evidence that gadolinium, in any form, had crossed the BBB. Only McDonald, et al. (5) found gadolinium deposits in the brain interstitium, even if a much larger fraction was observed in the endothelial walls.
The BCSFB is the morphological correlate of the BBB and is found at the level of unique apical tight junctions between the choroid plexus epithelial cells. These tight junctions inhibit paracellular diffusion of water-soluble molecules across this barrier (15). In addition to its barrier function, choroid plexus epithelial cells have a secretory function and produce the CSF. The barrier and secretory function of the choroid plexus epithelial cells are maintained by the expression of numerous transport systems that allow the directed transport of ions and nutrients into the CSF and the removal of toxic agents from the CSF. Unlike the BBB, the BCSFB is selectively permeable and it has been hypothesized that the BCSFB could allow the passage of GBCAs, or other gadolinium compounds, under certain conditions (17). CSF SI changes following administration of GBCAs have been observed with major disruptions of the BBB in studies involving neurologic disorders such as ischemic stroke, epilepsy, tumors, and acute brain injuries (17, 19, 20). Significantly reduced renal function has been described as a predisposing condition leading to elevated gadolinium compounds (a form never determined) in the CSF (21). However, the increased SI in the DN and GP on unenhanced T1-weighted MR images was shown to be independent of renal function status (1, 8). Thus, apart from repeated exposure to some, though not all, GBCAs, no other predisposing factors have been identified and it is not clear how gadolinium can get to and be retained in the brain interstitium.
Abnormal T1 shortening in the DN and GP on unenhanced images was observed in some patients exposed to repeated prior administration of some linear GBCAs and a macrocyclic GBCA. This imaging finding was associated with the presence and higher concentrations of gadolinium in these deep brain areas. The majority of gadolinium deposits have been observed in the endothelial walls, with a smaller fraction in the brain interstitium. No signs of neuronal damage could be observed at microscopy of the involved brain tissues. It is not clear in which form gadolinium is retained in brain tissues and which form may contribute to the effect on SI. Differently from NSF, which is observed exclusively in patients with severely reduced renal function, no groups of patients likely to be at increased risk of gadolinium accumulation in the brain have been identified. No clinical conditions have been associated with progressively increased SI in the GP and DN on unenhanced T1-weighted brain images. So far, no specific clinical guidelines on how to manage patients requiring multiple exposures to GBCAs have been released by any scientific society or regulatory authority.
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