MRI Contrast Agents - ESPR...Ireland UCD Radiography & Diagnostic Imaging UCD School of Medicine Aims and Objectives •Evaluation of the history and evolution of the clinical applications

UCD Radiography & Diagnostic ImagingUCD School of Medicine

MRI Contrast AgentsAndrea Cradock,

University College Dublin,

Ireland


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


Clinical Applications

Gadolinium Based Contrast Agents


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


The Basics

The mechanism of MR contrast agents

Paramagnetic Paramagnetic

Superparamagnetic


The gadolinium ion


Why is free gadolinium toxic?

Gd 3+ Ca 2+

Ion diameter: 1.08Å

Ion diameter: 1.14Å


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


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®


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


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.


Ionic

Linear Macrocyclic

Non-Ionic

Linear Macrocyclic

Nephrogenic Systemic Fibrosis

Very late adverse reaction


Categories

Ionic Non-ionic

Macrocyclic Dotarem®

Prohance®

Gadovist®

Linear

Magnevist®

Multihance®

Primovist®

Vasovist®

Omniscan®

Optimark®


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


N N

N N

Gd 3+

-O2C

-O2C

CO2-

CO2-

Cage like structure

Gd3+

Macrocyclic Chelator

Gadoterate


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


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


EMA Assessment report for

Gadolinium –containing

contrast agents

2010

Ionic

Linear Macrocyclic

Non-Ionic

Linear Macrocyclic


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


• 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


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


Recommendation from European Medicines Agency,

July 2017

Macrocyclic Linear

Dotarem Prohance Gadovist PrimovistSafety profile

not established<18

Magnevist Multihance Omniscan Optimark

✓ ✓ ✓ ✓


November 23, 2017

• European Commission confirm the recommendations from the EMA

• Legally binding and applicable to all EU member states.


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


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


• Nephrogenic Systemic Fibrosis

• At risk patients

• Linear V Macrocyclic

• Gadolinium deposition within the brain

✓

✓

✓

✓

• Clinical Significance ?


• 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


• Colleagues in Our Lady’s Children’s Hospital Crumlin

Acknowledgements



• 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


• 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


• 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

MRI Contrast Agents - ESPR...Ireland UCD Radiography & Diagnostic Imaging UCD School of Medicine Aims and Objectives •Evaluation of the history and evolution of the clinical applications

Documents