Aurelio Secinaro, MD

aurelio.secinaro@opbg.net

Pediatric MRI: How Gd retention has affected the choices of radiologists in daily clinical practice

• NATURE OF NON-CLINICAL EVIDENCE

~ 30 papers including Gd quantification,

speciation, T1 hyperintensity, histology

assessment, behavioural assessments, fetal

and perinatal assessments

• NATURE OF CLINICAL EVIDENCE

~ 60 papers on T1 hyperintensity

~ 70 review papers/commentary9 pathology papers (autopsy/biopsy)

Gd retention in the brain

23 November 2017 . . .

The macrocyclic agents

• ProHance, Gadovist & Dotarem structures are similar

• Hydroxypropyl (HP) group on ProHance molecule replaced by trihydroxybutyl (BT) group on Gadovist molecule

ProHance Gadovist Dotarem / Clariscan

0

1

2

3

4

5

6

7

MultiHance Gadovist ProHance Dotarem Magnevist Optimark Omniscan

6.2

4.64.4

3.94.3

4.5 4.4

@ 1.5 T

MR contrast agent - Relaxivity

Shen Y, et al. Invest Radiol 2015; 50:330-338

XXXX

0

1

2

3

4

5

Gadovist ProHance Dotaremr1 r

ela

xivi

ty

Maravilla KR et al. AJNR 2017; 38:1681-88

Comparisons of macrocyclic GBCA efficacy

Dotarem Gadovist

ProHance Gadovist

Maravilla KR et al. AJNR 2015; 36:14-23

Clearance from the brain – the glymphatic system

• Following IV injection, all GBCAs enter the CSF, possibly at the choroid plexus (CP)• Subarachnoid CSF enters the brain rapidly, along the perivascular spaces surrounding the penetrating arteries

(Virchow-Robin spaces)• GBCAs enter the brain interstitial fluid (ISF) through water channels called aquaporin 4 (AQP4) expressed by

astrocytes (CSF-ISF exchange)• Clearance of soluble proteins, waste products (GBCA species included), and excess extracellular fluid occurs

by convective ISF bulk flow towards the perivascular space around venous drainage system and, ultimately, to cervical lymph nodes (“the lymphatic drainage of the brain”, or “”glymphatic system”)

Entry of GBCAs into the brain

Two barriers:

Blood-Brain Barrier

Blood-CSF Barrier

24h after injection

McDonald RJ, et al. Radiology 2017; 285:536-545

Class dependent differences in Gd retention?

Gd concentrations in rat tissues after 7 days

Independent study

• 8 i.v. injections at 1.8 mmol/kg (4 per week). Equivalent to a triple standard dose in humans

• Gd concentratioons determined at 5, 26 and 52 weeks by ICP-MS

Long-term retention . . .

Jost G, et al. Radiology 2019; 290:340-348

• 5 rat weeks ~ 3 human years

• 26 rat weeks ~ 15 human years

• Less Gd is retained in the first weeks/months after ProHance

Sengupta P. The Laboratory Rat: Relating Its Age With Human's. Int J Prev Med 2013; 4:624-630

Long-term retention . . .

Aime S. Radiology. 2019; 291:267-268.

Differences in Gd retention among macrocyclic GBCAs?

Wrong!!!

Wrong!!!

Macrocyclic GBCAs: differences in Gd retention

Bussi S, et al. JMRI 2018; 47:746-752

Animals administered 20 GBCA injections over 5 weeks at 0.6 mmol/kg bodyweight per injection followed by 28 days recovery

Dotarem / Clariscan ProHance Gadovist

Possible reasons for lower Gd retention with ProHance

Charge Negative Neutral Neutral

Molecular weight 558.6 558.7 604.7

Log P butanol:water

-2.87 -1.98 -2.0

Viscosity (mPa·s) 2.0 [0.5 M] 1.3 [0.5 M] 4.96 [1.0 M]

• More rapid clearance of ProHance likely due to low molecular size, highest lipophilicity, lowest viscosity.

• Fewer interactions with surrounding matrix → more rapid clearance

• Fewer hydrogen bonds with ProHance than with Gadovist• Fewer electrostatic interactions with ProHance than with Dotarem

ProHance < Gadovist/Dotarem

Significantly lower Gd concentrations for ProHance

compared to Dotarem, Clariscan and Gadovist in the

cerebellum, cerebrum, and kidneys confirmed in

another still unpublished animal study

Confirmation of minimal retention with ProHance in multiple tissues

Organ Clariscan Dotarem Gadovist ProHance

Cerebellum 0.345 ± 0.0525 0.315 ± 0.0400 0.316 ± 0.0397 0.151 ± 0.0393

Cerebrum 0.377 ± 0.0421 0.342 ± 0.0448 0.292 ± 0.0473 0.144 ± 0.0147

Femur 9.44 ± 4.01 6.28 ± 3.08 16.1 ± 4.51 8.48 ± 1.87

Kidneys 294 ± 127 172 ± 134 212 ± 121 38.6 ± 25.0

Liver 0.823 ± 0.495 0.685 ± 0.330 1.22 ± 0.664 0.361 ± 0.106

Skin 0.688 ± 0.215 0.660 ± 0.202 0.999 ± 0.442 0.400 ± 0.112

Not yet published data

Macrocyclic GBCAs: differences in Gd retention Submitted for publication

* p<0.05

** p<0.01

*** p<0.005

Lower Gd levels in animal brain tissues after ProHance

McDonald et al., 2017 Jost. et al., 2018

Dosing 7 Days

Dosing 28 Days

Dosing 365 Days

35 Days

182 Days

Dotarem ProHance Gadavist

McDonald RJ et al.Radiology. 2017; 285:536-545

Bussi S, et al. JMRI 2018; 47:746-752

Jost G, et al. Radiology 2019; 290:340-348

GBCAs and the pediatric brainReference GBCA No of patients

No of Administra

tions (mean)

MR Scanner

MR Sequence

MeasurementsNo of time-

points

No of pts with visible

hyperintensityRT

Increased SI ratio

Other prior GBCA

Hu et al (Ped. Rad. 2016)

Magnevist ® 21 (2-14 ys) 4-36 1.5 T1SEGP,Th,DN,Caudate/

reference ROI: c. callosum.

1st-lastall > 10

administrations)NA yes

not excluded

Flood et al (Radiology 2016)

Magnevist ®30 & 16 (2mo-18

ys)6 1.5

MPRAGE & T1SE

GP/Th & DN/P 1st-last NA NOonly in DN

compared to HC and 1st and last

NO

Roberts et al (AJNR 2016)

Magnevist ®16 & 13 (2mo-14

ys)7.6 1.5-3 T1SE DN/C & DN/P

1st-last & longitudinal

all > than 7 administrations

NO yes not

excluded

Rossi Espagnet et al (Ped.Rad.2017)

Dotarem ® 50 (2-18) 10 3 T1SEGP/TH (50 pt) & DN/P

(26pt)

1st-last & longitudinal

l0 YES yes NO

Radbruch et al (Radiology 2017)

Dotarem ® 41 (1-17ys) 8.6 1.5 MPRAGE DN/P & DN/MCP 1st-last NA YES noNot

excluded

Tibussek(Radiology 2017)

Dotarem® &/or Prohance®

24 (2-14 ys) 14 1.5 MPRAGE GP/Th & DN/P SN case vs controls NA NO no NO

Schneider (AJNR) Multihance ® 34 & 24 (0-17ys) 8 1.5 T1SE GP/Th & DN/P 1st-last 0 NO no NO

Ryu (Inv Rad 2018)Ominscan® /Magnevist®

& Dotarem®41 vs 51 (0-14ys) 4 1.5 T1SE GP/Th & DN/P

1st-last & longitudinal

NA NO

Yes for linears in GP, DN in

Omniscan® group not

Magnevist®

NO

Renz et al (Inv. Rad. 2017)

Magnevist ® & Gadovist® 28 (0-17 ys) & 25

(2-17 ys)4 1.5 T1TSE GP/TH & DN/P & DN/MCP 1st-4th-last NA NO only with linear NO

Young et al (Clin. Rad. 2017)

All possible GBCA 41 (2-11 ys) 81.5-3

MPRAGE & T1SE

GP/Th & DN/P 1st-last &

longitudinal NA YES yes yes

GBCAs and the pediatric brain - limitations

• Single-center and retrospective in design: different selection criteria

• Differences in:

• patient populations (age <2ys and inclusion of NF1/LCH);

• image acquisition protocols (1.5-3T/MPRAGE-1.5T);

• methodology used for image evaluation (ROI/automatic);

• level, frequency and time of exposure to GBCAs;

• Correlations between qualitative and quantitative assessment;

• potential carryover effects deriving from previous exposures to different GBCAs.

• Association with other treatment (RT) and underlying clinical conditions (MS)

MRI & macrocyclic GBCA studies

Rossi Espagnet et al Ped. Rad 2017

DN/P SIR in 26 children (2-18 ys), mean of 10 MRI examinations with exclusive gadoterate

meglumine (Dotarem®) administration.

Pasquini et al Rad. Med. 2017

15 year-old boy with LLA

MRI & macrocyclic GBCA studies

Bjørnerud A, et al. Radiology. 2017;

MRI & macrocyclic GBCA studies

Patient with multiple sclerosis (MS) after 9

administrations of Gadovist®

Splendiani A. et al., Radiol Med. 2017

• No SI ratio difference was significantly greater than 0 (p > 0.01);

• Visible T1 hyperintensity in 1/3 of pts(>5 administrations).

Mithal et al Ped Rad. 2017

GBCAs and impact on clinical practice

58% (15/26) of pediatric radiology

departments surveyed switched their GBCA to the use of macrocyclic

agents only.

GBCAs and impact on clinical practice

Do we use GBCA administration when it is UNNECESSARY?

Do we NEED GBCA administrations?

Do we use GBCA administration when it is UNNECESSARY?

Düning et al. PedRad Apr.2018

• In pre-contrast NORMAL BRAIN MR relevant additional findings after CM inj. in 0.3% of pts = meningeal enhancement BUT only in 1/8 patients did this finding have a DIAGNOSTIC IMPACT on patient clinical work-up (i.e. not related to LP!)

3/million probability of missing a relevant meningeal enhancement in an otherwise normal MR

• In pre-contrast ABNORMAL BRAIN MR relevant additional findings after CM administration in 8.1% = meningeal enhancement, tumor spreading BEYOND pre-contrast abnormal findings in pt with SUSPECTED/KNOWN NEOPLASIA.

Maloney et al Ped Rad 2018

7 y.o. boy with anaplastic pineoblastoma(WHO grade IV)

1.9 yr f-up

CE-MRA 3D BB-TSE (SPACE) (systole) 3D SSFP (diastole)

3D Cardiovascular Sequences

New Evidence – GBCA Long-term effects?

4 Patients with Multiple Administration of Various GBCAs over 14 years

• diagnosed with GBM in 2004-2005

• Surgery, radiotherapy, chemotherapy

• Contrast-enhanced MRI first every month, later every two months, currently once a year

• Neurological examination focused on extrapyramidal symptomatology (2018)

• Neuropsychological examination (2018)

Courtesy of Prof. J. Vymazal, Department of Radiology, Na Homolce Hospital, Prague, Czech Republic

New Evidence (Case series)

Courtesy of Prof. J. Vymazal, Department of Radiology, Na Homolce Hospital, Prague, Czech Republic

Neurological and NeuropsychologicalExamination

No signs of rigidity in any patient

No signs of hypokinesis in any

patient

No signs of resting (or other) tremor

in any patient

Decreased synkinesia in one patient

Criteria for Parkinson Syndrome not

fulfilled in any patient

no progression of tracked symptoms

Prola-netto J, et al. Radiology 2018: 286:122-28

Limit of detection: 0.6 parts per trillion = 0.0003 x

10-5 %ID/g

(% injected maternal dose per gram x 10-5)

Gd in foetal tissues after maternal exposure to ProHance?

<60 parts per trillion

Technical

Conclusions

All GBCAs enter into the brain via the CSF in roughly equivalent amounts and rates

GBCA clearance from brain via the glymphatic pathway is dependent on the specific molecular properties

ProHance is cleared more rapidly resulting in lower overall Gd retention

More rapid clearance reflects more rapid diffusion through the ISF, possibly due to:

Smaller molecular size

Lower viscosity

Greater lipophilicity

Fewer interactions with surrounding matrix

Clinical Conclusions

Use of GBCAs should be avoided when not necessary.

Although no evidence of clinical consequences, Gd Retention scares more than NSF!!

MR native multiparametric imaging properties might reduce the need Gd administration in follow up studies

Macrocyclic CAs are generally safe and ProHance appears to have advantages

Thank youSpecial acknowledgments to Miles Kirchin and Camilla Rossi Espagnet