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Gadolinium Deposition Disease: A New Risk Management Threat

DOI:10.1016/j.jacr.2019.11.009
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H. Benjamin Harvey
H. Benjamin Harvey
H. Benjamin Harvey
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Vrushab Gowda at Harvard University
Vrushab Gowda
Glen Cheng at Harvard Medical School
Glen Cheng
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Abstract

Gadolinium-based contrast agents (GBCA) have enjoyed wide use since their introduction some 30 years ago. Used in as many as 30% of MRIs performed in the United States, GBCAs have generally been associated with low rates of adverse events. However, the safety profile and attendant medicolegal liability associated with GBCAs changed dramatically in 2016 with the description of gadolinium deposition disease (GDD). Despite being unproven scientifically, a groundswell of GDD-related litigation and personal injury advertising targeting potential GDD patients has occurred. In this article, we describe what GDD is, (2) why GDD has created medicolegal risk, and (3) how can this risk can be mitigated. This article advocates using a risk mitigation strategy focused on reducing brain gadolinium retention during the GDD-sensitive period of the first 2 months post-GBCA administration. As such, the authors recommend the use of gadoteridol as the default GBCA and administering other GBCAs, including linear agents, only when clinically necessary.
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ORIGINAL ARTICLE nLeadership
Gadolinium Deposition Disease: A New
Risk Management Threat
H. Benjamin Harvey, MD, JD
a,b,c
, Vrushab Gowda, BS
d
, Glen Cheng, MD, JD
a,e
Abstract
Gadolinium-based contrast agents (GBCAs) have enjoyed wide use since their introduction some 30 years ago. Used in as many as 30%
of MRIs performed in the United States, GBCAs have generally been associated with low rates of adverse events. However, the safety
profile and attendant medicolegal liability associated with GBCAs changed in 2016 with the description of gadolinium deposition
disease (GDD). Despite being unproven scientifically, a groundswell of GDD-related litigation and personal injury advertising targeting
potential GDD patients has occurred. In this article, we describe what GDD is, why GDD has created medicolegal risk, and how this
risk might be mitigated. This article advocates using a risk mitigation strategy focused on reducing brain gadolinium retention during the
period of purported GDD development. As such, based on the currently available data, the authors recommend the preferential use of
gadoteridol as the default GBCA for MRI imaging.
Key Words: Gadolinium, gadolinium deposition disease, lawsuit, liability, risk management
J Am Coll Radiol 2019;-:---. Copyright ª2019 American College of Radiology. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
INTRODUCTION
Contrast agents further enhance the diagnostic power of
MRIs and have found particular application in angiography
and oncologic imaging. Structurally, they consist of a linear
or macrocyclic carrier ligand chelated to a paramagnetic
metal ion, which serves to reduce T1 relaxation time and
facilitate visualization of perfused structures. These com-
pounds most commonly contain gadolinium(III) as the
active material, although iron oxide–and manganese-based
agents are also employed [1]. Gadolinium-based contrast
agents (GBCAs) have enjoyed wide use since their intro-
duction some 30 years ago, with some 450 million doses
administered worldwide to date [2]. They are generally well
tolerated and associated with lower rates of adverse events
than iodinated contrast agents [3].
Despite their ubiquity, GBCAs are not without their
risks. Alongside hypersensitivity reactions, acute nephro-
toxicity, and transient encephalopathy, nephrogenic sys-
temic fibrosis (NSF) has been identified as a potentially
debilitating process associated with GBCA exposure [4]. A
newly proposed pathology joined this complement in
2016: gadolinium deposition disease (GDD) [5].
Although shrouded in controversy as to its
pathophysiologic mechanism, modifiable risk factors, and
even existence as a disease in its own right, GDD has
grown salient in the public eye—a fact not lost on
personal injury attorneys.
The increasing risk exposure created by the advent of
GDD bears far-reaching implications for health systems,
referring physicians, and radiologists. This article surveys the
landscape facing these stakeholders by answering three
questions: What is GDD? Why does GDD create medico-
legal risk? How can this risk be mitigated?
FROM DEPOSITION TO DISEASE:
CORRELATION OR CAUSATION?
It has long been known that GBCA administration leaves
behind residual gadolinium. Studies have demonstrated its
uptake in various tissues, including bone, kidney, and the
brain, even in patients with an intact blood-brain barrier,
a
Harvard Medical School, Boston, Massachusetts.
b
Massachusetts General Hospital Department of Radiology, Boston,
Massachusetts.
c
Massachusetts General Hospital Institute for Technology Assessment,
Boston, Massachusetts.
d
Harvard Law School, Cambridge, Massachusetts.
e
Harvard T.H. Chan School of Public Health, Environmental and Occu-
pational Medicine and Epidemiology.
Corresponding author and reprints: H. Benjamin Harvey, MD, JD,
Department of Radiology, Massachusetts General Hospital, Institute for
Technology Assessment, 175 Cambridge Street, Suite 200, Boston,
MA 02114; e-mail: hbharvey@partners.org.
The authors state that they have no conflict of interest related to the ma-
terial discussed in this article.
Copyright ª2019 American College of Radiology. This is an open accessarticle under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1546-1440/19/$36.00 nhttps://doi.org/10.1016/j.jacr.2019.11.009 1
preserved renal function, and normal hepatic clearance [6-
8]. Interestingly, gadolinium preferentially deposits within
the brain in the dentate nuclei and globi pallidi, perhaps
conveyed to these structures through the recently
discovered glymphatic system [9,10]. Although both linear
and macrocyclic GBCAs alike collect within the brain,
linear agents (eg, gadopentetate, gadobenate, gadodiamide,
gadoxetate) are particularly prone to deposition [11,12].
Researchers have only recently suggested a potential
pathological consequence to this deposition in patients
with normal renal function.
In 2016, Semelka et al first described a constellation of
self-reported symptoms in patients with normal renal
function who had received GBCAs [5]. Suggesting causation
from correlation, the authors postulated this
symptomatology to represent GDD and went on to
propose diagnostic criteria for this newly proposed disease.
To meet the diagnostic criterion for GDD, a patient must
exhibit at least three of the following five broad symptom
clusters within a period of hours to 2 months post-GBCA
administration: (1) peripheral neuropathic pain in either a
“glove and stocking”or generalized distribution; (2) joint
stiffness, muscle spasms, buzzing sensation, and fatigue; (3)
headache; (4) clouded mentation; and (5) distal extremity
and skin substrate thickening, discoloration, and pain
[5,13]. Furthermore, it was proposed that GDD may
clinically manifest after the initial infusion of GBCA or
after multiple administrations in a dose-dependent manner
[14,15].
GDD is still only a proposed disease process with no
clear proof of its true existence. Nonetheless, theories con-
cerning the pathophysiological basis of this proposed disease
continue to be floated. Some have postulated that gadolin-
ium competitively inhibits calcium channels, thereby
interfering with proper neurologic function [16,17]. Others
suggest that GDD symptomatology may causally depend on
impaired heavy metal metabolism, itself a consequence of
heredity [18]. Similar to other heavy metal toxicities,
chelation treatment has been proposed for GDD.
However, in the absence of a proven disease process, there
is no clear evidence to support chelation treatment at this
time [19].
GDD, although still unproven, has nonetheless resulted
in an impressive regulatory and industry response. Shortly
following the initial description of GDD, the ACR and the
American Society of Neuroradiology issued a position
statement concerning the use of GBCAs, calling for pro-
viders to consider “multiple factors . . . when selecting a
GBCA, including diagnostic efficacy, relaxivity, rate of
adverse reactions, dosing/concentration, and propensity to
deposit in more sensitive organs such as the brain”[20]. The
US FDA convened the Medical Imaging Drugs Advisory
Committee in May and September 2017, which yielded a
692-page transcript of meeting minutes. This panel
concluded with “fair uniformity that there is no evidence of
a causal relationship between the symptoms and signs in
patients with normal renal function and the retention of
gadolinium”[21]. Despite this statement, the FDA took the
remarkable step of requiring imaging centers to distribute
patient Medication Guides to better apprise patients of
GBCA-associated risks prior to administration [22]. The
European Medicines Agency went one step further by
restricting the use of certain linear GBCAs, all the while
concluding that “there is currently no evidence that
gadolinium deposition in the brain has caused any harm
to patients”[23]. The glaring discordance between these
regulatory actions and the regulatory-convened scientific
panel statements of “no causality”is confusing for medical
practitioners, patients, and likely for juries. Laypeople can
easily misconstrue an overabundance of caution as
causation.
SYSTEMS-LEVEL SIGNIFICANCE: THE
ELEPHANT IN THE COURTROOM
Unlike NSF, GDD is marked by a significantly larger risk
footprint. The limited epidemiological understanding of this
proposed disease process does not permit a fine resolution of
population-level data at present. However, a recent study
has described a high prevalence of ‘GDD-like’symptom-
atology among patients receiving a GBCA. For instance, a
recent article from Parillo et al suggests that 13% of patients
who received the macrocyclic GBCA gadoterate meglumine
experienced ‘GDD-like’symptoms within the first 24 hours
after administration [24]. While not demonstrating causation,
the numbers are nonetheless alarming. Approximately 39
million MRI scans are performed in the United States each
year and as many as 12 million of these patients require
GBCA administration. Thus, if GDD liability were to
materialize, a pool of potential plaintiffs growing by over 1
million per annum is sufficiently large for institutional
actors to take heed. As such, large health systems are
increasingly making enterprise-level formulary switches pri-
marily to mitigate this risk exposure.
In the wake of NSF, personal injury attorneys are no
stranger to GBCA-based lawsuits. A simple web search will
show that many personal injury attorneys are already active
in the GDD space. Based on case characteristics alone, it is
likely that GDD cases will only proliferate over time [25].
There is a vast pool of potential plaintiffs, bearing low
costs of capture and still lower barriers to entry. Because
GDD clinical diagnostic criteria are largely subjective,
their existence is difficult to disprove [5]. Nonspecific and
transient constitutional, neurologic, and dermatologic
2Journal of the American College of Radiology
Volume -nNumber -nMonth 2019
features post-GBCA administration that extend beyond the
formal GDD diagnostic criteria may represent confounding
sources of symptomatology leading to an overdiagnosis of
‘GDD’post hoc [24]. And finally, the emergence of these
symptoms is dispersed over 2 months, which limits
diagnostic precision.
Notwithstanding the absence of a proven pathologic
mechanism of GDD, many courts have had to wrestle with
the viability of these claims. In multiple cases against
manufacturers, courts have repeatedly dismissed GDD-
based claims, citing amongst other issues inadequate evi-
dence of general causation between GBCAs and GDD
symptomatology [25]. This has led may other plaintiffs to
withdraw their claims voluntarily [26]. However, several
cases continue to work their way through the court
systems. With a growing corpus of GDD-related medical
literature, the concern arises that the new literature on
GDD, even if flawed methodologically, could in aggregate
suffice to pass the Daubert standard for expert testimony
[27], [28]. In turn, this would allow greater amounts
of expert testimony and technical evidence supporting
GDD-based claims into personal injury proceedings,
thereby increasing the viability of said claims.
The breadth of risk management exposure to physicians
and health systems remains uncertain. It is unclear if and
how far a GDD case against physicians or health systems
could proceed given that GBCA administration remains the
standard of care. Yet it remains plausible that GDD-based
claims against providers could have life if case theories assert
negligence in the choice of GBCA, i.e., choosing a GBCA
that results in greater brain gadolinium deposition than
necessary. ACR and ASNR opinions affirming the general
safety of these agents are unlikely to be dispositive in such
litigation. For instance, a review of cerebral palsy suits shows
that the American College of Obstetrics and Gynecology
professional opinion has not historically been accorded
decisive weight [29].
RISK MANAGEMENT STRATEGIES: REDUCING
BRAIN RETENTION DURING THE EARLY
WINDOW
Multiple varieties of GBCAs exist, each with differing risk
profiles.Thus,bychoosingtheright GBCA, radiologists
and referrers likely can reduce their risk exposure.
Experience from NSF lawsuits shows that litigation has
often been mitigated through the use of class II agents and
judicious estimated glomerular filtration rate precautions.
Although the ACR has yet to articulate specificpractice
recommendations, this article advocates adoption of a
similar approach to GBCA selection to mitigate the risk
of GDD.
To begin, macrocyclic GBCAs should be used over
linear agents whenever appropriate because it is well estab-
lished that the latter more avidly deposits within tissues such
as the brain and kidneys. Moreover, significant differences
between GBCAs also exist within the macrocyclic class of
GBCAs. Among macrocyclics, gadoteridol offers significant
advantages over its peers from a risk management perspec-
tive, with animal studies demonstrating significantly lower
retention and more efficient clearance in cerebral, cerebellar,
and renal tissue during the period of purported GDD
development [30,31]. These findings have been replicated in
recent well-conducted confirmatory studies and affirmed by
Hani Abujudeh, author of the textbook Quality and Safety
in Radiology and one of the first radiologists to describe NSF
[12,32,33]. In a recent review article, Dr Abujudeh noted
that “an increasing number of health systems [are
switching] to gadoteridol given its markedly lower levels of
gadolinium retention in the brain and kidneys”[34]. The
risk management benefits of gadoteridol have also been
extolled by attorney and risk management expert Dr
Nicholas Argy [35].
From a practical standpoint, a data-driven strategy of
risk mitigation grounded in the well-conducted studies
described above is likely to be simultaneously palatable,
attractive, and straightforward to both patients and potential
juries. Thus, based on the current data, we endorse a
strategy for risk mitigation based on the use of gadoteridol as
the default GBCA for MRI imaging. Such an approach aims
to minimize gadolinium retention in the brain during the
GDD-sensitive time window of the first 2 months post-
administration. However, this approach should not be
construed as a bright-line rule. Providers should not hesitate
to use other GBCAs, including linear agents, when clinically
advisable, such as with hepatic or tumor imaging. Given the
lack of clear evidence of GDD, it seems unnecessary and
even premature to implement an informed consent process
at this time. As an alternative, shared decision making tools
could prove both helpful to patients and reduce the risk of
possible GDD-related litigation down the road [35].
One perverse reality of this risk management issue is that
the radiologists and referring physicians who are exposed to
GDD-related liability are often not the individuals tasked
with making the GBCA decision. To compound this
problem, institutional GBCA decisions often factor in
financial considerations (i.e., cost-to-charge ratio). However,
exposing patients to more gadolinium for a financial gain is
unlikely to be well received by a jury if evidence for GDD
starts to mount. As such, physicians should communicate to
the pharmacy staff, clinical administrators, and risk man-
agers who make the enterprise-level formulary decisions the
importance of considering GDD-related liability when
selecting a GBCA. Moreover, whatever the GBCA choice,
Journal of the American College of Radiology 3
Leadership nHarvey, Gowda, Cheng nGadolinium Deposition Disease
health systems should be able to offer an evidence-based
defense of their GBCA selection that goes beyond a dollar
saved.
CONCLUSION
Although the science of GDD is uncertain at best, health
care providers would nonetheless be well advised to proac-
tively guard against GDD and its attendant liability. The
benefits of a risk mitigation strategy could be substantial—
including averting costly and disruptive litigation. Based on
the current data and regulatory statements, this article ad-
vocates for a risk mitigation strategy focused on reducing
brain gadolinium retention during the period of purported
GDD development in the first two months after GBCA
administration. As such, the authors recommend the use of
gadoteridol as the default GBCA for MRI imaging, with
other GBCAs, including linear agents, reserved for when
clinically advisable. Caution in GBCA choice now could pay
high dividends by avoiding costly GDD claims down the
road.
TAKE-HOME POINTS
-Increasing risk exposure created by the advent of
GDD bears far-reaching implications for health sys-
tems, referring physicians, and radiologists.
-GDD, although still unproven, has nonetheless
resulted in an impressive regulatory and industry
response.
-Unlike NSF, GDD is marked by a significantly larger
risk footprint.
-The preferred risk mitigation strategy is focused on
appropriate usage of GBCAs and on reducing brain
gadolinium retention during the GDD-sensitive
period of the first 2 months when GBCAs are needed.
-The authors, in agreement with other risk manage-
ment experts, recommend the use of gadoteridol as the
default GBCA for MRI imaging.
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Leadership nHarvey, Gowda, Cheng nGadolinium Deposition Disease
... On the other hand, superparamagnetic iron oxide (SPIO) nanoparticles (NPs) as T 2weighted MRI NCAs present a negative image enhancement. 13,14 In addition, porous silicon nanomaterials have been deployed as MRI NCAs with biocompatibility and contrasting properties. Considerable shortening of T 2 and the moderate alteration of T 1 have been reported using these agents. ...
... However, they suffer from possible toxicity/adverse side effects and low stability. 13,123 Because of the abovementioned disadvantages/limitations, future studies ought to be undertaken for the design of novel biocompatible NCAs with clinical applications. For instance, Mn(II)-based NCAs were designed utilizing pyclen diacetate and ethoxybenzyl for specific liver MRI, with high relaxivity (excellent T 1 -weighted contrast) and extraordinary stability (no need for conjugation to hydrophobic ligands); they exhibited acceptable uptake in hepatocytes with low toxicity and strong liver-specific enhancement at a dose of 60 μmol kg −1 . ...
... Overall, the relaxivity of MRI NCAs can be affected by the number of water molecules coordinated to the paramagnetic metal ions of contrast agents; their exchange rate as well as the rotational correlation time and electronic relaxation rate of the coordinated paramagnetic metal ions are also crucial parameters. 13,124 One of the solutions for obtaining efficient MRI NCAs with combined clinical diagnosis and treatment potential is hybridization, as exemplified by the hybrid magnetite−carbon nanofiber materials that were introduced as MRI NCAs. These nanoagents exhibited effective water solubility and could be applied as negative MRI NCAs with an improved transverse relaxivity of ∼268 ± 13 mM s −1 , offering efficient and smart MRI theranostic agents at high magnetic fields. ...
Nanoscale Contrast Agents for Magnetic Resonance Imaging: A Review
Article
  • Aug 2022
Today, magnetic resonance imaging (MRI) is one of the most widely applied noninvasive clinical imaging modalities with excellent applicability in bio- and nanomedicine, particularly in specific detecting and high-quality three-dimensional imaging of tumors/cancers. In this context, the design of efficient nanoscale contrast agents (NCAs) for MRI with high magnetic relaxivity and specificity/selectivity has garnered immense interest deploying a variety of innovatively designed nanostructures. Some important characteristics of NCAs such as biocompatibility, improved relaxivity, high dispersibility, specific targeting, and low toxicity make them ideal candidates for imaging/biosensing applications. The hybridization and surface functionalization/modification of these materials by applying suitable functional groups/agents can help to improve their properties and multifunctionality. However, there is still a long way to go in the clinical applications of these nanoagents to serve as a substitute for Gd-based contrast agents or other commercial materials. Importantly, nanotoxicological and biosafety issues of these NCAs need to be systematically addressed both at pre- and clinical stages; construction of smart multifunctional NCAs with clinical diagnostic and imaging potentials is thus warranted. Herein, recent advancements related to the diagnostic and imaging applications of MRI NCAs are deliberated, focusing on important challenges and future directions. ACS Appl. Nano Mater
... Typical are joint and bone pain, clouded mentation and headache, tightness in extremities and soft tissue thickening (Semelka et al., 2016b). The proposed diagnostic criteria for GDD include at least three of the five following symptom clusters occurring within hours to 2 months after the administration of GBCAs: "(1) peripheral neuropathic pain in either a "glove and stocking" or generalized distribution; (2) joint stiffness, muscle spasms, buzzing sensation, and fatigue; (3) headache; (4) clouded mentation; and (5) distal extremity and skin substrate thickening, discoloration, and pain" (reported in (Harvey et al., 2020) and (Maecker et al., 2021a)). ...
... The reports by advocacy groups as well as the studies by Semelka et al. describing diagnostic criteria (Semelka et al., 2016b), which seem to be largely subjective, and potential therapeutic strategies have been controversially discussed by the scientific community (Harvey et al., 2020. Raczeck et al. is summarizing that the existence of GDD is doubtful due to missing evidence but, however, cannot be scientifically disproven (Raczeck et al., 2019). ...
... The divergent decisions by the agencies have been criticized by the scientific community as confusing for medical practitioners as well as patients (Harvey et al., 2020). Raczeck et al. points out that retention of Gd was confirmed after both, linear and macrocyclic GBCAs, and therefore a restriction of only one class by the EMA is scientifically hard to explain. ...
Drug monitoring of Gadolinium-based MRI contrast agents in rats: neurobehavioral, histological, and biochemical findings
Thesis
  • Jan 2022
Gadolinium-based contrast agents (GBCAs) are widely used in clinical magnetic resonance imaging (MRI) since the mid-1980s. Recently, concerns have been raised since abnormal signal increases on magnetic resonance images as well as trace amounts of gadolinium (Gd) were detected in the brain even years after GBCA application. The genesis, form of the retained Gd, and reversibility of this accumulation of Gd within the deep cerebellar nuclei and the Globus pallidus (GP) of the central nervous system (CNS) are still not fully explained. Especially clinically relevant consequences and potential comorbidity of the phenomenon are of greatest interest to assess the safety of the routinely used compounds. The American Food and Drug Administration (FDA) as well as the European Medicines Agency (EMA) prompted all manufacturers of GBCAs as well as the scientific community to thoroughly investigate the phenomenon and to conduct vigilance studies. Following this official call, we assessed intermediate and long-term (5 – 52 weeks after the last injection) effects of multiple administrations of macrocyclic- (gadobutrol) and linear-chelated (gadodiamide) GBCAs in a rat model and studied neuro-histopathology as well as gene expression, and distribution of retained Gd in combination with a comprehensive behavioral phenotyping. As an established preclinical model, healthy male Wistar-Han rats received either 8 injections of 0.6, 1.2 or 1.8 mmol/kg BW gadobutrol, gadodiamide or saline as a control. Using a hypothesis-free study design, a broad range of behavioral domains including general health and metabolic status, motor function, emotion, sensorimotor function, nociception and cognition were investigated longitudinally for up to 52 weeks post GBCA administration (p.i.). Tissue samples were taken 11, 35 and 54 weeks p.i. for further assessment of the neuropathology. Mirroring the clinical situation, laser ablation inductively coupled plasma-mass spectrometry (LA-ICP-MS) revealed retention of Gd in the Nucleus dentatus (DN) of animals treated with gadodiamide. This long-term outcome was associated with an early intermittent and reversible reduction of the startle reaction to acoustic stimuli around 7 weeks p.i. Grooming behavior of gadodiamide animals, measured in the OpenField test 5 weeks p.i., was increased due to dermatitis-like skin lesions and loss of fur, known to be occurring with high doses of linear GBCAs. In general, conducted tests for motor function, cognition, nociception as well as the metabolic and emotional status of the animals were not affected by exposure to GBCAs. Gene expression profiling by RNA-sequencing as well as the stereologically assessed number of NeuN-positive cells in the deep cerebellar nuclei revealed no apparent differences 11 weeks p.i. Subcellular fractionation of brain tissue revealed, that Gd seems to co-enrich especially in synaptosomes of animals treated with gadodiamide. The detected amount of Gd found in synaptosomes of rats with exposure to gadobutrol was smaller, and in addition the intact form of gadobutrol was detected exclusively. In contrast, in synaptosomes extracted from brain tissue of gadodiamide animals insoluble Gd as well as high molecular weight species were found in addition to the intact GBCA. These results point to some form of dechelation of the less stable GBCA gadodiamide in vivo with (subsequent) binding to certain molecules prone to act as polyanionic acceptors for Gd3+ cations, eventually resulting in high-relaxivity complexes that are able to cause the visible hyperintensities on MR images. New, and to some extend surprising, expression sites of the extracellular matrix and perineuronal net (PNN) protein aggrecan, representing a polyanionic acceptor for (dissociated) Gd3+, partially overlapped with sites of deposited Gd, as revealed by combined application of immunohistology and LA-ICP-MS. Taken together, this study revealed that repeated GBCA application of gadodiamide at clinically relevant dosage induce a transient reduction in acoustic startle response in rats. Sites of GBCA retention overlap partially with PNN proteins but retention of Gd in the DN was neither associated with a general pathway deregulation nor neuronal cell loss. The findings described in this work have been partially published in in the peer-reviewed journal Scientific Reports by Habermeyer et al. (Habermeyer et al., 2020). Our preclinical studies yield a caveat for the clinical use of linear GBCAs and should challenge further research in the direction of PNN-GBCA interactions as well as the effect of GBCAs on the (peripheral) sensory nervous system.
... Therefore, both DCE and DSC MRI may be insensitive to the early minor changes and subsequently insensitive to early disease detection [11]. The safety aspect of gadolinium has been a matter of concern as it may cause severe side effects such as nephrogenic systemic fibrosis, nausea, headache, renal dysfunction, neurotoxicity, etc. [12][13][14][15]. A non-invasive alternative MRI approach is more appealing for assessing BBB in both healthy people and patients. ...
Arterial Spin Labelling-Based Blood-Brain Barrier Assessment and Its Applications
Article
  • Dec 2022
The brain relies on the blood-brain barrier (BBB) for the selective absorption of nutrients and the exclusion of other big molecules from the circulating blood. Therefore, the integrity of BBB is critical to brain health, and assessing BBB condition is of great clinical importance. BBB is often examined using exogenous tracers that can travel across the BBB, but the tracers might cause severe side effects. To avoid the use of external tracers, researchers have used magnetically labeled arterial blood as the endogenous tracer to assess the water permeability of BBB as a surrogate index of BBB. This paper reviews the three major types of Arterial Spin Labelling (ASL) based BBB water permeability assessment techniques and their applications in brain diseases such as Alzheimer's Disease.
... 29 MRI is a noninvasive imaging method widely used in clinical medicine that involves non-ionizing radiofrequency pulses and magnetic fields to generate threedimensional images. Contrast-enhancement is used in roughly 30% of all MRI scans, 30 and contrast agents include paramagnetic ions that influence the relaxation rates of nearby water protons to lead to changes in contrast within MR images. As a contrast agent, Eu II is oxidized to non-contrast-enhancing Eu III in the presence of oxygen, leading to bright, contrastenhanced images only in reducing environments, making complexes of Eu II uniquely suited to image oxygen-deficient environments. ...
Systemic Delivery of Divalent Europium from Ligand Screening with Implications to Direct Imaging of Hypoxia
Article
Full-text available
  • Dec 2022
Hypoxia is a hallmark of many diseases, including cancer, arthritis, heart and kidney diseases, and diabetes, and it is often associated with disease aggressiveness and poor prognosis. Consequently, there is a critical need for imaging hypoxia in a noninvasive and direct way to diagnose, stage, and monitor the treatment and development of new therapies for these diseases. Eu-containing contrast agents for magnetic resonance imaging have demonstrated potential for in vivo imaging of hypoxia via changes in metal oxidation state from +2 to +3, but rapid oxidation in blood limits EuII-containing complexes to studies compatible with direct injection to sites. Here, we report a new EuII-containing complex that persists in oxygenated environments and is capable of persisting in blood long enough for imaging by magnetic resonance imaging. We describe the screening of a library of ligands that led to the discovery of the complex as well as a pH-dependent mechanism that hinders oxidation to enable usefulness in vivo. These studies of the first divalent lanthanide complex that persists in oxygenated solutions open the door to the use of EuII-based contrast agents for imaging hypoxia in a wide range of diseases.
... Although opinions may differ, we propose that, ideally, an AMRI imaging surveillance protocol should be non-invasive (i.e., no intravenous contrast agent administration) with an examination time comparable to that of US (ten to fifteen minutes), but with improved detection capabilities of HCC compared with US. Concerns on the possible long-term risks with repeated use of gadolinium-based MRI contrast agents in a surveillance setting, with possible accumulation of Gadolinium in the brain, combined with the added benefit of non-invasiveness and lower costs, would thus make NC-AMRI the preferred choice over CE-AMRI protocols [32][33][34]. Possible further reductions in patient handling time and/or costs resulting from the omission of intravenous contrast-agent injection from the MRI screening protocol are beyond the scope of this study. Nonetheless, patient-in-room time of our proposed NC-AMRI protocol is relatively comparable to the time needed for an US examination. ...
Potential of a Non-Contrast-Enhanced Abbreviated MRI Screening Protocol (NC-AMRI) in High-Risk Patients under Surveillance for HCC
Article
Full-text available
  • Aug 2022
Purpose: To evaluate NC-AMRI for the detection of HCC in high-risk patients. Methods: Patients who underwent yearly contrast-enhanced MRI (i.e., full MRI protocol) of the liver were included retrospectively. For all patients, the sequences that constitute the NC-AMRI protocol, namely diffusion-weighted imaging (DWI), T2-weighted (T2W) imaging with fat saturation, and T1-weighted (T1W) in-phase and opposed-phase imaging, were extracted, anonymized, and uploaded to a separate research server and reviewed independently by three radiologists with different levels of experience. Reader I and III held a mutual training session. Levels of suspicion of HCC per patient were compared and the sensitivity, specificity, and area under the curve (AUC) using the Mann-Whitney U test were calculated. The reference standard was a final diagnosis based on full liver MRI and clinical follow-up information. Results: Two-hundred-and-fifteen patients were included, 36 (16.7%) had HCC and 179 (83.3%) did not. The level of agreement between readers was reasonable to good and concordant with the level of expertise and participation in a mutual training session. Receiver operating characteristics (ROC) analysis showed relatively high AUC values (range 0.89-0.94). Double reading showed increased sensitivity of 97.2% and specificity of 87.2% compared with individual results (sensitivity 80.1%-91.7%-97.2%; specificity 91.1%-72.1%-82.1%). Only one HCC (2.8%) was missed by all readers. Conclusion: NC-AMRI presents a good potential surveillance imaging tool for the detection of HCC in high-risk patients. The best results are achieved with two observers after a mutual training session.
... in the setting of an intact blood-brain barrier (63,64). Although the clinical significance of residual gadolinium remains unclear, caution is required, and the risks versus benefits of GBCA use must be weighed carefully, particularly in patients with Fontan circulation who are likely to undergo repeated administrations over time. ...
Performance of Cardiac MRI in Pediatric and Adult Patients with Fontan Circulation
Article
  • Jun 2022
Cardiac MRI has become a widely accepted standard for anatomic and functional assessment of complex Fontan physiology, because it is noninvasive and suitable for comprehensive follow-up evaluation after Fontan completion. The use of cardiac MRI in pediatric and adult patients after completion of the Fontan procedure are described, and a practical and experience-based cardiac MRI protocol for evaluating these patients is provided. The current approach and study protocol in use at the authors' institution are presented, which address technical considerations concerning sequences, planning, and optimal image acquisition in patients with Fontan circulation. Additionally, for each sequence, the information that can be obtained and guidance on how to integrate it into clinical decision-making is discussed. Keywords: Pediatrics, MRI, MRI Functional Imaging, Heart, Congenital © RSNA, 2022.
Ferumoxytol-Enhanced Cardiac Magnetic Resonance Angiography and 4D Flow: Safety and Utility in Pediatric and Adult Congenital Heart Disease
Article
Full-text available
  • Nov 2022
Cardiac magnetic resonance imaging and angiography have a crucial role in the diagnostic evaluation and follow up of pediatric and adult patients with congenital heart disease. Although much of the information required of advanced imaging studies can be provided by standard gadolinium-enhanced magnetic resonance imaging, the limitations of precise bolus timing, long scan duration, complex imaging protocols, and the need to image small structures limit more widespread use of this modality. Recent experience with off-label diagnostic use of ferumoxytol has helped to mitigate some of these barriers. Approved by the U.S. FDA for intravenous treatment of anemia, ferumoxytol is an ultrasmall superparamagnetic iron oxide nanoparticle that has a long blood pool residence time and high relaxivity. Once metabolized by macrophages, the iron core is incorporated into the reticuloendothelial system. In this work, we aim to summarize the evolution of ferumoxytol-enhanced cardiovascular magnetic resonance imaging and angiography and highlight its many applications for congenital heart disease.
Imaging
Chapter
  • Sep 2022
Inorganic chemistry has had a large impact on both clinical and preclinical imaging, and this chapter describes the contribution of inorganic chemistry to various imaging modalities. The chapter is divided into sections by modality. Each section introduces an imaging technique then describes recent highlights from 2017 through early 2021 and important historical examples of the impact of inorganic chemistry on the imaging technique in the section. Imaging modalities covered in this chapter include X-ray computed tomography, optical and near-IR imaging, magnetic particle imaging, ultrasound and photoacoustic imaging, magnetic resonance imaging, and positron emission tomography and single-photon emission computed tomography. This chapter is intended to be an introduction to the use of inorganic chemistry in imaging, and also provides references to thorough reviews on specific subtopics within each section.
Practice Management Strategies for Imaging Facilities Facing an Acute Iodinated Contrast Media Shortage
Article
  • May 2022
An unanticipated but severe shortage in iodinated contrast media (ICM) is currently affecting imaging practices across the globe and is expected to persist through at least the end of June 2022. This supply shock may lead to healthcare systems experiencing an acute imaging crisis, as many affected facilities have contrast agent supplies that are anticipated to last only a week or two under normal operating conditions. To maximize the opportunity to continue to provide optimal care for patients with emergent or life-threatening imaging indications and thereby minimize the overall impact on patient care, practice leaders will need to quickly assess their contrast material inventories, prioritize examination indications, and reduce their expected short-term usage of ICM. This Clinical Perspective reviews ICM conservation techniques that we have deployed, or are considering deploying, depending on the severity and length of the supply shortage.
Macrocyclic MR contrast agents: evaluation of multiple-organ gadolinium retention in healthy rats
Article
Full-text available
  • Dec 2020
Objectives: The purpose of this study was to compare Gd levels in rat tissues after cumulative exposure to four commercially available macrocyclic gadolinium-based contrast agents (GBCAs). Methods: Sixty-five male Sprague-Dawley rats were randomized to four exposure groups (n = 15 per group) and one control group (n = 5). Animals in each exposure group received 20 GBCA administrations (four per week of ProHance®, Dotarem®, Clariscan™, or Gadovist® for 5 consecutive weeks) at a dose of 0.6 mmol/kg bodyweight. After 28-days' recovery, animals were sacrificed and tissues harvested for Gd determination by inductively coupled plasma-mass spectroscopy (ICP-MS). Histologic assessment of the kidney tissue was performed for all animals. Results: Significantly (p ≤ 0.005; all evaluations) lower Gd levels were noted with ProHance® than with Dotarem®, Clariscan™, or Gadovist® in all soft tissue organs: 0.144 ± 0.015 nmol/g vs. 0.342 ± 0.045, 0.377 ± 0.042, and 0.292 ± 0.047 nmol/g, respectively, for cerebrum; 0.151 ± 0.039 nmol/g vs. 0.315 ± 0.04, 0.345 ± 0.053, and 0.316 ± 0.040 nmol/g, respectively, for cerebellum; 0.361 ± 0.106 nmol/g vs. 0.685 ± 0.330, 0.823 ± 0.495, and 1.224 ± 0.664 nmol/g, respectively, for liver; 38.6 ± 25.0 nmol/g vs. 172 ± 134, 212 ± 121, and 294 ± 127 nmol/g, respectively, for kidney; and 0.400 ± 0.112 nmol/g vs. 0.660 ± 0.202, 0.688 ± 0.215, and 0.999 ± 0.442 nmol/g, respectively, for skin. No GBCA-induced macroscopic or microscopic findings were noted in the kidneys. Conclusions: Less Gd is retained in the brain and body tissues of rats 28 days after the last exposure to ProHance® compared to other macrocyclic GBCAs, likely due to unique physico-chemical features that facilitate more rapid and efficient clearance.
Nephrogenic Systemic Fibrosis: A Review of History, Pathophysiology, and Current Guidelines
Article
Full-text available
  • Feb 2019
Purpose of Review Nephrogenic systemic fibrosis (NSF) is a rare systemic disease with a high mortality. The purpose of this review is to provide clinicians with guidance regarding safe administration of GBCAs to patients with renal disease. Summary Development of NSF has been linked to the administration of gadolinium-based contrast agents (GBCAs) in patients with renal disease. Due to the wide variety of available GBCAs and recommendations regarding safe administration of these agents, it can be difficult for clinicians to choose the best GBCA for this patient population. Recent Findings Although the current ACR guidelines have virtually eliminated the risk of NSF, future research may lead to the development of alternative contrast agents for patients at risk of NSF who require contrast-enhanced MRIs.
Long-term Excretion of Gadolinium-based Contrast Agents: Linear versus Macrocyclic Agents in an Experimental Rat Model
Article
Full-text available
  • Nov 2018
Purpose To investigate the long-term course of MRI signal intensity (SI) changes and the presence of gadolinium in the rat brain during a 1-year period after multiple administrations of gadolinium-based contrast agents (GBCAs). Materials and Methods Rats received a linear GBCA (gadodiamide, gadopentetate dimeglumine, gadobenate dimeglumine), a macrocyclic GBCA (gadobutrol, gadoterate meglumine, gadoteridol), or saline. Animals received eight injections over 2 weeks (1.8 mmol/kg per injection). Brain MRI and gadolinium measurements were performed with inductively coupled plasma mass spectrometry (ICP-MS) and laser ablation ICP-MS 5, 26, and 52 weeks after administration. Results Animals that received linear GBCAs showed higher deep cerebellar nuclei (DCN)-to-brainstem SI ratios compared with the saline group (P < .001 at all time points). After 1 year, mean gadolinium concentrations in the cerebellum were 3.38 nmol/g (gadodiamide), 2.13 nmol/g (gadopentetate dimeglumine), and 1.91 nmol/g (gadobenate dimeglumine). For linear agents, laser ablation ICP-MS revealed gadolinium depositions in the cerebellar nuclei. For macrocyclic GBCAs, the DCN-to-brainstem SI ratios did not significantly differ from those in the saline group (P > .42) and the cerebellar gadolinium concentrations decreased between weeks 5 and 52, reaching 0.08 nmol/g (gadobutrol), 0.04 nmol/g (gadoterate meglumine), and 0.07 nmol/g (gadoteridol). The respective laser ablation ICP-MS analysis showed no gadolinium depositions. Conclusion Increased signal intensity in the deep cerebellar nuclei of rats persists for at least 1 year after administration of linear gadolinium-based contrast agents (GBCAs), in line with persistent brain gadolinium concentrations with no elimination after the initial 5-week period. The animals that received macrocyclic GBCAs showed an ongoing elimination of gadolinium from the brain during the entire observation period. © RSNA, 2018.
Gadolinium Deposition in Brain: Current Scientific Evidence and Future Perspectives
Article
Full-text available
  • Sep 2018
In the past 4 years, many publications described a concentration-dependent deposition of gadolinium in the brain both in adults and children, seen as high signal intensities in the globus pallidus and dentate nucleus on unenhanced T1-weighted images. Postmortem human or animal studies have validated gadolinium deposition in these T1-hyperintensity areas, raising new concerns on the safety of gadolinium-based contrast agents (GBCAs). Residual gadolinium is deposited not only in brain, but also in extracranial tissues such as liver, skin, and bone. This review summarizes the current evidence on gadolinium deposition in the human and animal bodies, evaluates the effects of different types of GBCAs on the gadolinium deposition, introduces the possible entrance or clearance mechanism of the gadolinium and potential side effects that may be related to the gadolinium deposition on human or animals, and puts forward some suggestions for further research.
Cumulative gadodiamide administration leads to brain gadolinium deposition in early MS
Article
  • Jul 2019
Objective: Frequent administration of gadolinium-based contrast agents in multiple sclerosis (MS) may increase signal intensity (SI) unenhanced T1-weighted imaging MRI throughout the brain. We evaluated the association between lifetime cumulative doses of gadodiamide administration and increased SI within the dentate nucleus (DN), globus pallidus (GP), and thalamus in patients with early MS. Methods: A total of 203 patients with MS (107 with baseline and follow-up MRI assessments) and 262 age- and sex-matched controls were included in this retrospective, longitudinal, 3T MRI-reader-blinded study. Patients with MS had disease duration <2 years at baseline and received exclusively gadodiamide at all MRI time points. SI ratio (SIR) to pons and CSF of lateral ventricle volume (CSF-LVV) were assessed. Analysis of covariance and correlation analyses, adjusted for age, sex, and region of interest volume, were used. Results: The mean follow-up time was 55.4 months, and the mean number of gadolinium-based contrast agents administrations was 9.2. At follow-up, 49.3% of patients with MS and no controls showed DN T1 hyperintensity (p < 0.001). The mean SIR of DN (p < 0.001) and of GP (p = 0.005) to pons and the mean SIR of DN, GP, and thalamus to CSF-LVV were higher in patients with MS compared to controls (p < 0.001). SIR of DN to pons was associated with number of gadodiamide doses (p < 0.001). No associations between SIR of DN, GP, and thalamus and clinical and MRI outcomes of disease severity were detected over the follow-up. Conclusions: DN, GP, and thalamus gadolinium deposition in early MS is associated with lifetime cumulative gadodiamide administration without clinical or radiologic correlates of more aggressive disease.
Contrast media and cutaneous reactions. Part 1. Immediate hypersensitivity reactions to contrast media and gadolinium deposition
Article
  • May 2019
Contrast media (CM) are commonly used worldwide to enhance the quality of imaging, which is invaluable for diagnostic accuracy. Adverse reactions to CM are uncommon, but frequently involve cutaneous symptoms. This two‐part article reviews adverse events secondary to CM that are relevant to the practising dermatologist. Part 1 will classify CM, address immediate hypersensitivity reactions and review the newly described condition, gadolinium deposition disease. Part 2 will cover the delayed hypersensitivity reactions of iodinated contrast medium including severe cutaneous adverse reactions and iododerma.
Evaluating the Patient with Reported Gadolinium-Associated Illness
Article
  • Nov 2018
Introduction Gadolinium-based contrast agents (GBCAs) have been increasingly used in clinical practice since their introduction in the 1980s. Recently, increased public attention has been given to patients who report new symptoms following GBCA exposure. This review details the current knowledge surrounding GBCAs, with a focus on the known and proposed disease states that may be associated with GBCAs. Recommendations for the appropriate clinical workup of a patient suspected of having symptoms attributable to gadolinium exposure are included. Discussion GBCAs are known to precipitate the disease state nephrogenic systemic fibrosis (NSF), a syndrome characterized by skin thickening in patients with preexisting renal disease. An additional syndrome, termed gadolinium deposition disease, has been proposed to describe patients with normal renal function who develop an array of symptoms following GBCA exposure. While there is a potential physiologic basis for the development of this condition, there is no conclusive evidence to support a causal relationship between GBCA administration and the reported symptoms yet. Clinical evaluation revolves around focused history-taking and physical examination, given the absence of a reliable link between patient symptoms and measured gadolinium levels. There are no recommended treatments for suspected gadolinium deposition disease. Chelation therapy, which is not approved for this indication, carries undue risk without documented efficacy. Conclusions The extent to which GBCAs contribute to clinically relevant adverse effects remains an important and evolving field of study. NSF remains the only proven disease state associated with GBCA exposure. Additional data are required to evaluate whether other symptoms should be attributed to GBCAs.
A Structured Survey on Adverse Events Occurring Within 24 Hours After Intravenous Exposure to Gadodiamide or Gadoterate Meglumine: A Controlled Prospective Comparison Study
Article
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.
Gadolinium deposition and the potential for toxicological sequelae - A literature review of issues surrounding gadolinium-based contrast agents: Gadolinium deposition
Article
  • Jul 2018
Every year, approximately 30 million magnetic resonance imaging (MRI) scans are enhanced with gadolinium-based contrast agents (GBCAs) worldwide. Although the development of nephrogenic systemic fibrosis in patients with renal impairment is well-documented, over recent years it has become apparent that exposure to GBCAs can potentially result in gadolinium deposition within human bone and brain tissue even in the presence of normal renal function. This review will address some of the controversies surrounding the safety of GBCA administration based on evidence from in vivo experiments, animal studies, and clinical studies. We additionally evaluate the potential risk of toxicity from exposure to gadolinium in light of new guidance published by the US Food and Drug Administration and the European Medicines Agency, and discuss whether gadolinium deposition disease exists as a 'new' diagnosis.