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Update on Gadolinium depositions in the brain
PD Dr. med. Assessor juris Alexander RadbruchRadiology, DKFZ
Disclosures
• Guerbet (consultant, financial study support, advisory boards, lectures)
• Bayer (consultant, financial study support, advisory boards, lectures)
• GE (advisory board, expert opinion)• Bracco (advisory board)• Siemens (lectures)• Prime Oncology (lectures)• AbbVie (advisory board)
Satbility of GBCAs
Gadolinium in freeform: toxic
Hence: Gadolinium boundto a chelate
Idee et al , Role of Thermodynamic and Kinetic Parameters in Gadolinium Chelate Stability, JMRI 30:1249–1258 (2009)
Port M et al, Biometals 2008 Aug;21(4):469-90
Satbility of GBCAs
A B
Frenzel T. et al , In vitro release of Gd3+ by GBCAs incubated in native Human serum at 37°C,Investigative Radiology 2008
linear, non-ionic
linear, ionic
macrocyclic
Satbility of GBCAs
December 2013: Kanda I
Kanda et al, High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-weighted MR Images: Relationship with IncreasingCumulative Dose of a Gadolinium based Contrast Material, Radiology 2014
Hyperintensities after serialGBCA injections in patientswithout impaired renal function
• 19 patients with ≥ 6 serial injectionsOmniscan/Magnevist
• 16 patients with ≥ 6 unenhanced MRIs
Kanda I et al
Kanda et al, High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-weighted MR Images: Relationship with IncreasingCumulative Dose of a Gadolinium based Contrast Material, Radiology 2014
„Kanda Lesions“
1. Kanda Dec 2013 Radiology Omniscan/Magnevist
2. Errante Oct 2014 Invest. Radiology Omniscan
3. Kanda II Jan 2015 Radiology Magnevist vs Prohance
4. Quattrocchi March 2015 Invest. Radiology Omniscan
5. Radbruch I Apr 2015 Radiology Magnevist vs Dotarem
6. Ramalho I June 2015 Radiology Omniscan vs Multihance
7. Stojanov June 2015 Eur. Radiology Gadovist
8. Adin August 2015 AJNR macrocyclic and linear GBCAs
9. Weberling Sept 2015 Invest. Radiology Multihance
10. Radbruch II Nov 2015 Invest. Radiology Gadovist
11. Cao Febr. 2016 AJR Gadovist vs Magnevist
12. Tedeschi Febr. 2016 Eur. Radiology macrocyclic and linear GBCAs
13. Ramalho II Febr. 2016 Eur. Radiology Omniscan, subsequentlyMultihance
Retrospective Patient Studies
• 38 patients withmultiple scllerosiswith ≥2 serialinjections
• 37 patients with brainmetastases with ≥2 serial injections
Multiple Sclerosis
Errante et al, Progressive Increase of T1 Signal Intensity of the Dentate Nucleus on Unenhanced Magnetic Resonance Images Is Associated With Cumulative Doses of Intravenously Administered Gadodiamide in Patients With Normal Renal Function, Suggesting Dechelation, Investigative Radiology 2014
Brain Mets
Errante 2014 (Omniscan - linear)
• 46 Meningiomapatients
• 3 groups: • 1 enhanced scan (10
patients) • < 6 enhanced scans
(28 patients) • ≥ 6 enhanced scans (8
patients)
Quatrocchi et al, Gadodiamide and Dentate Nucleus T1 Hyperintensity in Patients With Meningioma Evaluated by Multiple Follow-Up Contrast-Enhanced Magnetic Resonance Examinations With No Systemic Interval Therapy, Investigative Radiology 2014
1st scan 5th scan 10th scan
Quatrocchi 2014 (Omniscan - linear)
• 23 patients at least 2 enhanced MRI withMagnevist
• 36 patients at least 2 enhanced MRI withProhance
Kanda II et al, High Signal Intensity in Dentate Nucleus on Unenhanced T1-weighted MR Images: Associationwith Linear versus Macrocyclic Gadolinium Chelate Administration, Radiology 2015
7 prior injections of Magnevist 15 prior injections of Prohance
Kanda II 2015: Magnevist (linear)vs Prohance (macrocyclic)
• 50 Patienten (mostlyglioma) in 2 groups
• ≥ 6 serial injections ofvon magnevist orDotarem
• Accumulated dosis162.41 ± 45.20 (Dotarem) 124.22 ±39.31 (Magnevist)
• multivariate analysis forDN-pons
Radbruch et al, Gadolinium Retention in the Dentate Nucleus and Globus Pallidus Is Dependent on the Class of Contrast Agent, Radiology 2015
1st
1st Magnevist
1st Dotarem 6th Dotarem
6th Magnevist
Radbruch I 2015 Magnevist (linear) vsDotarem (makrozyklisch)
Weberling et al, Investigative Radiology 2014
• 50 patients (malignantmelanoma), ≥ 5 serialinjections of Multihance
• DN - Pons und DN - CSF
• 7.7 ± 3.2 examinations
Prior and after 15 injectionsof Multihance
Please have a look at your PACS-Station!
Weberling 2015Multihance (linear)
• In contrast: Ramalho I/II et al no SI increase
• But: 4.6 ± 2.1 / 4.5 ± 2.0 examinations withMultihance
Ramalho I et al, Radiology 2015, Ramalho II et al European Radiology 2016
Stojanov et al, Increasing signal intensity within the dentate nucleus and globus pallidus on unenhanced T1W magnetic resonance images in patients withrelapsing-remitting multiple sclerosis: correlation with cumulative dose of a macrocyclic gadolinium-based contrast agent, gadobutrol, Euro. Radiology 2015
• 58 patients with multiple sclerosis
• 4.74±0.72 injections of Gadovist• Significant Increase DN - Pons (p<0.001)
Stojanov 2015 Gadovist (macrocyclic)
Radbruch et al, High-Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-Weighted Images Evaluation of the Macrocyclic Gadolinium-Based Contrast Agent Gadobutrol, Investigative Radiology 2015
• 30 patients (glioma), ≥ 5 seriaelGadovist Injections
• 7.3 ± 3.1 scans (Stojanov et al 4.74±0.72 scans )
• Accumulated dosage 54.1 ± 30.4 ml (Stojanov et al 33.26±11.27 ml)
Prior and after 19 injections of Gadovist
Radbruch II 2015 Gadovist (macrocyclic)
makrozyklisch
1.Errante
2. Kanda II Prohance
3. Quattrocchi
4. Radbruch I Dotarem
5. Ramalho
6. Stojanov Gadovist
7. Weberling
8. Radbruch II Gadovist
9. Cao Gadovist
10. Ramalho II
Summary: RetrospectivePatient Studies – macrocyclic GBCAs
T1-SI Increase
No T1-SI Increase
makrozyklisch
1.Errante
2. Kanda II Prohance
3. Quattrocchi
4. Radbruch I Dotarem
5. Ramalho
6. Stojanov Gadovist
7. Weberling
8. Radbruch II Gadovist
9. Cao Gadovist
10. Ramalho II
T1-SI Increase
No T1-SI Increase
Summary: Retrospective Patient Studies – macrocyclic GBCAs
makrozyklisch
1.Errante
2. Kanda II Prohance
3. Quattrocchi
4. Radbruch I Dotarem
5. Ramalho
6. Stojanov Gadovist
7. Weberling
8. Radbruch II Gadovist
9. Cao Gadovist
10. Ramalho II
T1-SI Increase
No T1-SI Increase
No case of a visible signal intensity increaseafter serial injections of macrocyclic GBCAs
is documented!
Prior and after 19 Iinjections of Gadovist
Summary: Retrospective Patient Studies – macrocyclic GBCAs
1.Errante Omniscan
2. Kanda II Magnevist
3. Quattrocchi Omniscan
4. Radbruch I Magnevist
5. Ramalho Omniscan Multihance
6. Stojanov
7. Weberling Multihance
8. Radbruch II
9. Cao Magnevist
10. Ramalho II Omniscan Multihance
T1-SI Increase
No T1-SI Increase
Summary: RetrospectivePatient Studies – linear GBCAs
1.Errante Omniscan
2. Kanda II Magnevist
3. Quattrocchi Omniscan
4. Radbruch I Magnevist
5. Ramalho Omniscan Multihance
6. Stojanov
7. Weberling Multihance
8. Radbruch II
9. Cao Magnevist
10. Ramalho II Omniscan Multihance
T1-SI Increase
No T1-SI Increase
Multihance
Zusammenfassung: Retrospektive Patientenstudien – lineare GBCAs
1.Errante Omniscan
2. Kanda II Magnevist
3. Quattrocchi Omniscan
4. Radbruch I Magnevist
5. Ramalho Omniscan Multihance
6. Stojanov
7. Weberling Multihance
8. Radbruch II
9. Cao Magnevist
10. Ramalho II Omniscan Multihance
T1-SI Increase
No T1-SI Increase
Multihance
• 4.6 ±±±± 2.1 Injections of Multihance• “significant trend towards increase”
DN:MCP (P = .013)
Prior and after 15 injections ofMultihance
• Significant SI increase p<.001• 7.7 ±±±± 3.2 Injections Multihance
• No significant SI increase• “carry over effect”?• 4.5 ±±±± 2.0 Injections Multihance
All retrospective patient studies forlinear GBCAs have shown a signalintensity increase (exception: Ramalho I and II for Multihance ≤ 4,6 Injektionen Multihance)
Summary: RetrospectivePatient Studies – linear GBCAs
Jost et al., Investigative Radiology; Nov 2015
• 10 Injections over 2 weeks
• 2.5 mmol Gd/kg bodyweight
• Linear GBCAs:• Magnevist• Multihance• Omniscan
• Macrocyclic GBCAs:• Dotarem• Gadovist
Animal Study I: Jost et al (2015)Assessment of Signal Intensity Increase
Results of animal studies about signal intensity increase are in accordance with the retrospective patient studies!
• 20 Injektionen von 0.6 mmol Gd/kg
• Linear GBCAs:• Magnevist• Multihance• Omniscan
• MacrocyclicGBCAs:
• Dotarem
Robert et al., Investigative Radiology; Nov 2015
Animal Study II: Robert et al (2015)Assessment of Signal Intensity Increase
Gadolinium-Assessment in Cerebellum: Significant difference between lineare GBCAs to Saline, but not to the macrocyclic Dotarem.
• 20 Injections of von 0.6 mmol Gd/kg
• Linear GBCAs:• Magnevist• Multihance• Omniscan
• MacrocyclicGBCAs:
• Dotarem
Animal Study II: Robert et al (2015)Measurement of Gadolinium
Robert et al., Investigative Radiology; Nov 2015
McDonald et al, Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging, Radiology 2015
Correlation of the cumulative gadolinium dosage, T1-Signal Intensity Increase and gadolinium concentration in the tissue
Histopathological correlation study: McDonald et al (2015) – Omniscan (linear)
Mass-spectroscopy in brain tissue of decesed patients
GBCA group (Omniscan) (n=13) ≥ 4 Injections
controll Gruppe(n=10)≥ 1 unenhanced
scan
• Cluster of Ggadolinium in endothelium
• No “gross histologic changes” between contrast and control groups
McDonald et al, Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging, Radiology 2015
Histopathological correlation study: McDonald et al (2015) – Omniscan (linear)
Murata et al, Macrocyclic and Other Non–Group 1 Gadolinium Contrast Agents Deposit Low Levels of Gadolinium in Brain and Bone Tissue Preliminary Results From 9 Patients With Normal Renal Function, Investigative Radiology 2015
Mass Spectroscopy in brain and bone tissue tissue of deceased patients
2 patients Gadovist
1 patient Multihance
1 patient Eovist
5 patients Prohance
CAVE: Possible confounder:: pior GBCA applications
Deposition in the bone 23 times higher than in Dentate Nucleus: Tip of the Iceberg?
Murata et al: Noconclusions can bedrawn from this small sample size
20 times lower Prohance deposition compared to Omniscan (McDonald)
Histopathological Correlation Studies:Murrata et al (2016)
1. Correlation between cumulative intravenous injection ofGBCA and gadolinium tissue, T1-signal increase (DN)
2. Deposition also in other parts of the brain and the bone(Murata et al: 23 times higher in the bone)
3. Differences between linear and macrocyclic GBCA (only 5 patients!): Omniscan (McDonald et al) deposited20 times more gadolinium than Prohance (Murata et al)
4. All GBCAs deposit a certain amount of Gadolinium. 5. No gross histologic changes proven, yet.
Histopathological Correlation Studies:Summary
Clinical Correlates?
Barbieri et al, High signal intensity in dentate nucleus and globus pallidus on unenhanced T1-weighted MR images in three patients with impaired renal function and vascular calcification, Contrast Media & Molecular Imaging
No clear clinical Correlates are proven, yet.
Anecdotal report: Barbieri et al:
- 3 Patients with impaired renal function and hyperintensities in DN and GP:
- “transient signs of neurological disorders of undetermined cause”
Anecdotal report: Miller et al:
- 35 injections of Magnevistbetween the ages 8 and 20
- Hyperintensities in DN and GP
- „neuropsychological testingsuggests difficulties with executivefunctioning“
Miller et al, MRI Brain Signal Intensity Changes of a Child During the Course of 35 Gadolinium Contrast Examinations, Pediatrics 2015
Abstract ECR 2016:B-0196 Forslin et al: - “23 MS patients, 18-year follow-up, and 24 age-/gender-matched controls”- “Increased SI index in the DN was associated with decreased performance in cognitive tests
(-0.008, P=0.02)”
Current Situation
• GBCAs can be life-saving medication
• appr. 300 million injections with a very good safety profile
• No imaging technique that is currently available can adequately replace contrast enhanced MR.
Recommendation NIH
1.GBCAs should be used only when clinically indicated or when specified in an institutional review boarde approved protocol.
2.When GBCAs are required, consider the use of a macrocyclic GBCA (eg, gadobutrol, gadoteridol, gadoterate meglumine) rather than a linear agent.
3.For patients with documented sensitivity (eg, hives) to macrocyclic agents, it is appropriate to use linear agents when clinically indicated.
4.MRI protocols should always consider FDA label indicationsand dosing schemes for administration of GBCAs.
5.Encourage intra- and interdepartmental research programs toevaluate T1 shortening in the brain and other organs in patients who have received multiple doses of GBCAs.
Malyeri et al, National Institutes of Health Perspective on Reports of Gadolinium Deposition in the Brain, 2016
In the media in Germany:
• “Gadolinium deposition might be connected with Alzheimer or Dementia”
• “Cardiovascular MRI can be replaced by myocardial scintigraphy”
• No differentiation between macrocyclic and linear GBCA
The Public and the patient should be informed comprehensively:
• Clinical correlates are still unknown/unclear.• No case of a visible signal intensity increase after seria l
applications of macrocyclic GBCAs is documented, yet!
Danger of Gadolinium Phobia
Thank you foryour attention!