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UCD Radiography & Diagnostic ImagingUCD School of Medicine
MRI Contrast AgentsAndrea Cradock,
University College Dublin,
Ireland
UCD Radiography & Diagnostic ImagingUCD School of Medicine
Aims and Objectives
• Evaluation of the history and evolution of the clinical applications of Gadolinium based contrast agents (GBCA)
• Outline of the physiochemical characteristics and biodistribution pathways of GBCA
• Current safety aspects and guidelines for the paediatric population
UCD Radiography & Diagnostic ImagingUCD School of Medicine
Clinical Applications
Gadolinium Based Contrast Agents
UCD Radiography & Diagnostic ImagingUCD School of Medicine
Requirements of an MR contrast agent
• Low concentration
• Predictable biodistribution
• Lack of reactivity within the body
• It should be stable
• Low viscosity
• Fulfills its role in imaging the tissue
UCD Radiography & Diagnostic ImagingUCD School of Medicine
The Basics
The mechanism of MR contrast agents
Paramagnetic Paramagnetic
Superparamagnetic
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The gadolinium ion
UCD Radiography & Diagnostic ImagingUCD School of Medicine
Why is free gadolinium toxic?
Gd 3+ Ca 2+
Ion diameter: 1.08Å
Ion diameter: 1.14Å
UCD Radiography & Diagnostic ImagingUCD School of Medicine
What is chelating
• A safe ‘chemical wrapper’
• Decreases the interactions with the human body
• Increases the speed of elimination from the body
• Regulate pharmokinetics
• Determines the bio distribution into the extracellular space and elimination pathway
Chelator
Ionic
Linear Macrocyclic
Non-Ionic
Linear Macrocyclic
Gadobenatedimeglumine
Gadoteratemeglumine Gadodiamide Gadobutrol
UCD Radiography & Diagnostic ImagingUCD School of Medicine
Ionic Linear
• Multihance®
• Magnevist ®
Ionic Macrocyclic
• Dotarem®
Non ionic linear
• Omniscan®
Non ionic macrocyclic
• Gadovist®
Behazdi et al (2018)-Reactions with Ionic > non ionic
Behazdi et al (2018)- Lowest rate of immediate reactions with Omniscan®
UCD Radiography & Diagnostic ImagingUCD School of Medicine
Types of adverse reactions
Acute
Chemotoxic
Allergic/hypersensitivity
Within 60 minutes
Late
1 hour – 1 week
Skin reactions not associated with GBCA
Very Late
> 1 week
Nephrogenic Systemic Fibrosis
UCD Radiography & Diagnostic ImagingUCD School of Medicine
Risk of Immediate Adverse reaction with GBCA
• A prior drug hypersensitivity reaction
• Prior reaction to a GBCA
• Asthma requiring medical treatment
• ?Premedication
• If increased risk consider alternative test and a different contrast agent should be considered
• Keep all patients that have received a dose in the department for 30 minutes.
UCD Radiography & Diagnostic ImagingUCD School of Medicine
Ionic
Linear Macrocyclic
Non-Ionic
Linear Macrocyclic
Nephrogenic Systemic Fibrosis
Very late adverse reaction
UCD Radiography & Diagnostic ImagingUCD School of Medicine
Categories
Ionic Non-ionic
Macrocyclic Dotarem®
Prohance®
Gadovist®
Linear
Magnevist®
Multihance®
Primovist®
Vasovist®
Omniscan®
Optimark®
UCD Radiography & Diagnostic ImagingUCD School of Medicine
N N N
-O2C
-O2C
CO2-
Gd 3+
Elongated organic molecular ligand that tightly wraps around
the ion
Gd3+
CO2-
CO2-
Gadopentatate dimeglumine
Linear Chelator
UCD Radiography & Diagnostic ImagingUCD School of Medicine
N N
N N
Gd 3+
-O2C
-O2C
CO2-
CO2-
Cage like structure
Gd3+
Macrocyclic Chelator
Gadoterate
UCD Radiography & Diagnostic ImagingUCD School of Medicine
Thermodynamic Stability
Kinetic Stability
The speed at which the chelated
gadolinium agent
dissociates
The amount of energy
required to release the
Gd3+ ion from the Gd-ligand
complex
Dissociation of Gd 3+ from chelate
Concentration of competing ions
Ions compete for the ligand (Zn, Fe3+ Mg2+
Cu2+ Ca2+ ) and ions compete
for the Gd(phosphate, carbonate)
Transmetallation
UCD Radiography & Diagnostic ImagingUCD School of Medicine
The Onset of NSF
• In Austria, Grobner et al (2006) described nephrogenic fibrosing dermatopathy (NFD) after the administration of certain contrast agents in patients suffering from end stage real failure
• In Denmark, Marckmann et al (2006) identified 13 patients who developed the same disease and looked for a causative factor
• Gadodiamide, Omniscan®, was used
UCD Radiography & Diagnostic ImagingUCD School of Medicine
EMA Assessment report for
Gadolinium –containing
contrast agents
2010
Ionic
Linear Macrocyclic
Non-Ionic
Linear Macrocyclic
UCD Radiography & Diagnostic ImagingUCD School of Medicine
Patients with renal impairment• may have more circulating Ca and Ph ions, thus increasing the risk
of transmetallation• Reduced clearance of chelate from the body• Renal function tests introduced• Paediatrics and neonates identified as ‘at risk groups’
– ‘High NSF risk’ GBCA’s contraindicated in neonates up to 4 weeks– All doses below 1 year of all GBCA’s should be carefully considered with
minimum 7 day interval administration.
• Reported in few paediatric settings– Nardone et al (2014) A RADAR report identified 23 reported cases of
paediatric NSF, with seventeen having documented exposure to GBCA in ages 6-18
Patient related risk factors
UCD Radiography & Diagnostic ImagingUCD School of Medicine
• Kanda et al (2014) first reported evidence of high signal intensity in the dentate nucleus and globuspallidus.
• Kanda et al (2015) found that it was associated with past linear chelate administration but not with macrocyclic administration.
2014
Gadolinium deposits
evident in the brain
Gadolinium deposition in a 10-year-old girl with spinal cord astrocytoma status post resection
Images Courtesy of Rozenfeld M., Podberesky, D. (2018) Gadolinium based contrast agents in children, Paediatric
Radiology, 48: 1188-1196.
Unenhanced T1 weighted images
UCD Radiography & Diagnostic ImagingUCD School of Medicine
Evidence of T1 hyperintensities from retrospective studies to date
Macrocyclic Linear
Dotarem Prohance Gadovist Primovist Magnevist Multihance Omniscan
✓ ✓ ✓ ✓
European Medicines Agency’s
Pharmacovigilance and Risk Assessment Committee (PRAC)Recommendations
March 21, 2017
UCD Radiography & Diagnostic ImagingUCD School of Medicine
Recommendation from European Medicines Agency,
July 2017
Macrocyclic Linear
Dotarem Prohance Gadovist PrimovistSafety profile
not established<18
Magnevist Multihance Omniscan Optimark
✓ ✓ ✓ ✓
UCD Radiography & Diagnostic ImagingUCD School of Medicine
November 23, 2017
• European Commission confirm the recommendations from the EMA
• Legally binding and applicable to all EU member states.
UCD Radiography & Diagnostic ImagingUCD School of Medicine
On going studies: gadolinium deposition
• Various studies have shown evidence of Gd deposition in the paediatric brain irrespective if renal function
• Diversity of results
• Some suggestions that MRI is not sensitive enough to demonstrate T1 hyperintensities associated with macrocyclic agents
• Animal studies found that deposition occurs in three forms-soluble small molecules, soluble macromolecules and insoluble gadolinium (Frentzel et al, 2017)
• Mode of deposition through the glymphatic system
UCD Radiography & Diagnostic ImagingUCD School of Medicine
Clinical significance of Gd accumulation
• Dentate nucleus responsible for planning, initiation and control of voluntary movements
• Globus Pallidus – regulation of voluntary movements
• What are the neurological implications? – Perrotta et al (2017) carried out a study on cerebellar
symptoms after serial administration of a macrocyclic agent. Results showed no sign of cerebellar toxicity
– McDonald R (RSNA, 2017) did not identify any cognitive decline, dementia or decline in motor performance
– Retrospective studies does not link it to Parkinson disease (Welk et al, 2016)
• Further prospective research required to confirm
UCD Radiography & Diagnostic ImagingUCD School of Medicine
• Nephrogenic Systemic Fibrosis
• At risk patients
• Linear V Macrocyclic
• Gadolinium deposition within the brain
✓
✓
✓
✓
• Clinical Significance ?
UCD Radiography & Diagnostic ImagingUCD School of Medicine
• These patients may be the population that see any long term effects
• ‘Gadolinium deposition disease’
• Administer with caution
• Be aware of any risk factors
• Lowest dose possible
• Radiology review of pre-contrast images
• Use of macrocyclic agents
• Review of protocols
Significance for the paediatric population.
In Summary
UCD Radiography & Diagnostic ImagingUCD School of Medicine
• Colleagues in Our Lady’s Children’s Hospital Crumlin
Acknowledgements
UCD Radiography & Diagnostic ImagingUCD School of Medicine
UCD Radiography & Diagnostic ImagingUCD School of Medicine
• Behzadi, AH., Zhao, Y., Farooq, Z., Prince, MR., (2018) Immediate Allergic Reactions to Gadolinium – Based Contrast Agents: A Systematic Review and Meta-Analysis, Radiology, 286 : 471
• Grobner, T (2006) Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrology Dialysis Transplantation, 21(4) : 1104-1108
• Markmann, P., Skov, L., Rossen, K., Dupont, A., Damholt, MB., Heaf, JG., Thomsen, H. (2006) Nephrogenic Systemic Fibrosis: Suspected Causative Role of Gadodiamide Used for Contrast-Enhanced Magnetic Resonance Imaging, Journal of American Society of Nephrology, 17 : 2359-2362
• Nardone, B., Saddleton, E., Laumann E et al (2014) Pediatric NephreogenicSystemic Fibrosis is rarely reported: A RADAR Report, Paediatric Radiology; 44:173-180
References
UCD Radiography & Diagnostic ImagingUCD School of Medicine
• Kanda, T., Ishii, K., Kawaguchi, H., Kitajima, K., Takenaka, D. (2014) High Signal Intensity in Dentate Nucleus on Unenhanced T1 Weighted Images : relationship with increasing cumulative dose of a gadolinium-based contrast material, 270 (3) : 834-841
• Kanda, T., Osawa, M., Oba, H., Toyoda, K., Haruyama, T., Takeshita, K., Furui, S. (2014) High Signal Intensity in Dentate Nucleus on Unenhanced T1 Weighted Images : Association with Linear versus Macrocyclic Gadolinium Chelate Administration, Radiology, 275 (3) : 803-809
• Ramalho, J; Castillo, M; AlObaidy, M; Nunes, RH; Ramalho, M; Dale, BM.; Semelka, RC. (2015) High signal intensity in globus pallidus and dentate nucleus on unenhanced T1-weighted MR images: evaluation of two linear gadolinium-based contrast agents. Radiology, 276, 836-844.
• Perrotta, G., Metens, T., Absil, J., Lemort, M., Manto, M (2017) Absence of clinical cerebellar syndrome after serial injectiosn of more than 20 doses of gadoterate, a macrocyclic GBCA: a monocenter retrospective study, Journal of Neurology, 264 : 2277-2283
References
UCD Radiography & Diagnostic ImagingUCD School of Medicine
• Frenzel et al (2017) Quamntification and assessment of the chemical form of residual gadolinium in the brain after repeated administration of gadolinium based contrast agents : comparative study in rats. Investigative Radiology, 52 : 255-264
References