1. Gadobenate dimeglumine (Multihance) deposition in the dentate nucleus and globus pallidus
Arian Mashhood MD PGY-4

2. Background: Gadolinium Deposition
Dentate Nucleus/Pons
Globus Pallidus/Thalamus
Dozen or so studies over the last two years
Pharma, societies talking about it
Top: (a) Scatterplot of dentate nucleus–to-pons signal intensity ratio versus number of previous gadolinium-based contrast material administrations. (b) Scatterplot of globus pallidus–to-thalamus signal intensity ratio versus number of previous gadolinium-based contrast material administrations. In each plot, solid line represents linear regression and dashed lines indicate 95% confidence limits.
Kanda et al. Radiology 2014

3. Background: GBCA Stability
Macro-
cyclic
Linear
Linear:
Macrocyclic:

4. Multihance vs other GBCAs
Multihance may bind to gadolinium better than other linear GBCAs
Limited human studies
Robert P, et al. Linear Gadolinium-Based Contrast Agents Are Associated With Brain Gadolinium Retention in Healthy Rats. Invest Radiol 2016 Feb; 51(2): 73-82
Add info on new study investigating single cadaveric case with multihance (check pdf for link)
Single study, single dose, no real effect noted
Robert et al. Invest Radiol 2016; Murata et al. Invest Radiol 2016

5. Hypothesis
Gadolinium deposition is demonstrated on pre contrast T1 and SWI sequences in the dentate nucleus and globus pallidus after multiple doses of Multihance.

6. Specific Aims
Primary aim: Demonstrate abnormal signal hyperintensity on pre-contrast T1 of the globus pallidus and dentate nucleus in patients who have received multiple doses of gadolinium as Multihance only.
Secondary aim: Demonstrate abnormal signal hypointensity on SWI of the globus pallidus and dentate nucleus in patients who have received multiple doses of gadolinium as Multihance only.

7. Study Data Inclusion/exclusion criteria > 4 doses Multihance only
1st and 4th or later dose must be a brain study
Pre-contrast T1 images before 1st ever contrast dose
Satisfactory anatomy
Pre-contrast T1 images 2 mm or thinner
Anatomy that allows analysis of at least one region of interest (DN or GP)

8. Demographics
21 test cases that met inclusion/exclusion criteria out of ~500 cases reviewed
15 male, 6 female
17 at 3T, 4 at 1.5T
Age 2-66 years old, mean 38.4 years old

9. Demographics Pathology Number of cases AVM Medulloblastoma GBM ADEM
Meningioma
Pituitary/pineal germinoma
Mastoiditis and sinus venous thrombosis
Subdural empyema
Neurocystecercosis
Ependymoma
Pituitary adenoma
Metastatic disease
Retinoblastoma
Toxoplasmosis 3 2 1

10. Data Collection
Previous studies have used signal intensity ratios of DN to pons, and GP to thalamus, to measure Gd deposition
Standardized size region of interest (ROI) drawn in the anatomic structures, and signal intensity values are collected, with the ratio calculated
Same process for T1 data as SWI data

11. Results: T1 DN/pons ratio GP/thalamus ratio p = .00008 p = .0001
Average number of doses: 5.4 for DN, 5.2 for GP, range of 4-8
p =
p = .0001
0 Doses Gd
> 4 Doses Gd
0 Doses Gd
> 4 Doses Gd

12. Results: SWI DN/pons ratio GP/thalamus ratio p = .80 p = .27
Average number of doses: 5.4 for DN, 5.2 for GP, range of 4-8
p = .80
p = .27
0 Doses Gd
> 4 Doses Gd
0 Doses Gd
> 4 Doses Gd

13. % Increase SI Ratio By GBCA
Discussion
Gadolinium deposition present in GP and DN
Clinical significance unknown
No significant difference in signal intensity ratios on SWI in either GP or DN
% Increase SI Ratio By GBCA
Omniscan
Magnevist
Dotarem
Multihance
Globus Pallidus
1-2% --
~0%
4.5 ± 0.2%
Dentate Nucleus
8-11%
4-5%
6.1 ± 0.3%
Time for contrast to wash out may be longer than thought
Gadodiamide – percent increase by # of doses

14. Discussion
Higher resolution SWI or more cases with SWI may validate the anecdotal observation of SWI hypointensity after several doses of gadolinium
Maybe mineralization, maybe some other natural effect, gadolinium may not be the dominant factor on SWI

15. Further Research
Comparison to gender, age, disease, and dose-matched control
Time since prior contrast administration
Radiation therapy
Cerebral radiation therapy has been shown in another study to have a statistically significant correlation to the gp/thalamus ratio

16. Acknowledgements
Samuel Barnes PhD Karen Tong MD Paggie Kim MD Udo Oyoyo PhD ISP Meeting Staff: Brenda Bartnik-Olson PhD, Sheri Harder MD, J Paul Jacobson MD, Barbara Holsouser PhD, Daniel Kido MD, Adina Achiriloaie MD Additional ISP Meeting Participants: Arsalan Ahmed MD, Chad Burk MD, Mohammad Kassir MD, Sam Nyon MD, Eric Peters MD, Johnny Suh MD, Alex Sun MD, Austin Trinh MD

17. Questions?