pediatric mri: how gd retention has affected the choices of ...€¦ · pediatric mri: how gd...
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Aurelio Secinaro, MD
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