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!