Central nervous system gadolinium accumulation in patients undergoing periodical contrast MRI screening for hereditary tumor syndromes

Abstract

BackgroundPatients with hereditary tumor syndromes undergo periodical magnetic resonance imaging (MRI) screening with Gadolinium contrast. Gadolinium accumulation has recently been described in the central nervous system after repeated administrations. The prevalence and rate of accumulation in different subgroups of patients are unknown. Neither are the mechanism nor clinical impact. This may cause uncertainty about the screening. To explore the prevalence and rate of Gadolinium accumulation in different subgroups, we retrospectively analyzed MRIs of patients with von Hippel-Lindau disease (VHL) and Tuberous Sclerosis Complex (TSC).MethodsWe determined the prevalence and rate of accumulation in the dentate nucleus and globus pallidus on unenhanced T1-weighted MRI from VHL and TSC patients. We compared the signal intensities of these regions to the signal intensity of the pons. We evaluated the impact of number of MRIs, kidney function and liver function on Gadolinium accumulation.ResultsTwenty eight VHL patients and 24 TSC patients were included. The prevalence of accumulation in the dentate nucleus and globus pallidus increased linearly according to number of Gadolinium enhanced MRIs and was higher in the VHL group (100%). A significant linear correlation between number of MRIs and increased signal intensity was observed in the VHL group.ConclusionsGadolinium accumulation occurs in almost all patients undergoing contrast MRI screening after >5 MRIs. We advocate a screening protocol for patients with hereditary tumor syndromes that minimizes the Gadolinium dose. This can be accomplished by using a single administration to simultaneously screen for brain, spine and/or abdominal lesions, using an MRI protocol focused on either VHL- or TSC-specific lesions. Higher prevalence and rate of accumulation in VHL patients may be explained by the typical vascular leakage accompanying central nervous system hemangioblastomas.

Gadolinium Deposition in Neurology Clinical Practice

“…13 Vergauwen et al conducted a retrospective study in a population of patients with either von Hippel-Lindau disease (n=28 subjects) or tuberous sclerosis complex (n=24 subjects) and discovered that both demonstrated increased signal on T1weighted images in the DN and GP, although the increase in the tuberous sclerosis complex group did not reach statistical significance. 11 Notably, detailed records of the identity of contrast agents used for this study were not available, but basing a conjecture on the agents used by the hospitals where the MRIs were performed, linear GBCAs (gadopentetate, gadodiamide, gadobenate) were likely predominately used, with the recent introduction of gadoterate in 2016 (2 years prior to publication). 11 In May 2017, the FDA announced that to date no harmful sequelae of gadolinium deposition in the brain had been identified but that reviews would continue.…”

“…11 Notably, detailed records of the identity of contrast agents used for this study were not available, but basing a conjecture on the agents used by the hospitals where the MRIs were performed, linear GBCAs (gadopentetate, gadodiamide, gadobenate) were likely predominately used, with the recent introduction of gadoterate in 2016 (2 years prior to publication). 11 In May 2017, the FDA announced that to date no harmful sequelae of gadolinium deposition in the brain had been identified but that reviews would continue. 42 In May 2018, the FDA announced that GBCAs would require new class warnings that detail the potential for gadolinium deposition.…”

“…Evidence shows that gadolinium is deposited in the DN and GP of the brain, as measured by autopsy, spectrometry, and MRI. [4][5][6][7][8][9][10][11][12]35,36,40,41 An example of the accumulation of gadolinium deposition is shown in Figure 2. Gadolinium deposition has been more prominently associated with linear than with macrocyclic GBCAs, 4,6,[8][9][10]13,36,40 possibly because of differences in kinetic and thermal stabilities.…”

“…However, several recent papers (1995-2018) have indicated that gadolinium has the potential to deposit and persist within the body, particularly within the dentate nucleus (DN) and globus pallidus (GP) of the brain. [2][3][4][5][6][7][8][9][10][11][12][13] While the long-term clinical significance of gadolinium deposition remains unclear, this discovery has many in the medical community reconsidering the applications and necessity of GBCAs. In this article, we review the peer-reviewed data on GBCA safety and deposition.…”

Potential of MRI in Radiotherapy Mediated by Small Conjugates and Nanosystems

“…Numerous studies over the last two decades have been dedicated to the design of Gd(III)-complexes with modulated number (q) and residence time (τ M ) of water molecules in the first coordination sphere and the rotational correlation time (τ R ) of the complex in order to increase the r 1 . Recently, an important safety concern has been raised in connection with possible release of toxic "free" Gd(III)-ions in vivo causing nephrogenic systemic fibrosis [17] or their accumulation in the central nervous system [18]. Therefore, every new design of a potential MRI CA molecule towards increased r 1 by optimization of the aforementioned parameters by chemical modifications requires thorough evaluation of the thermodynamic and kinetic stabilities of the final complex.…”