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

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

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

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

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

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.

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)

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

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

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

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 = .00008 p = .0001 0 Doses Gd > 4 Doses Gd 0 Doses Gd > 4 Doses Gd

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

% 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

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

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

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

Questions?