Table 2.

Review of literature of studies showing association between repeated administration of GBCAs and high T1 signal intensity in the dentate nucleus and globus pallidus

Study	Groups	Contrast agents	Remarks
Studies in adults
Kanda et al., 2014[7]	19 patients underwent >6 CE-MRI examinations; 16 patients underwent more than 6 unenhanced examinations	Gadopentetate-dimeglumine gadodiamide	High SI in the DN and GP with direct relation to number of examinations
Errante et al., 2014[11]	38 patients with MS underwent CE - >2 MRI scans; 37 patients with brain metastases underwent >2 CE-MRI scans	Gadodiamide	High SI in the DN and GP has a linear relationship with the CE-MRI in patients with MS and brain metastasis
Weberling et al., 2015[12]	50 patients underwent more than 5 CE-MRI	Gadobenate-dimeglumine	High SI in the DN
Adin et al., 2015[13]	184 patients with brain metastasis treated with brain irradiation underwent recurrent CE-MRI	Gadopentetate-dimeglumine	Repeated CE-MRI examinations shows persistent hyperintensity in the DN on unenhanced T1WI
Zhang et al., 2017[14]	13 patients who had undergone >30 CE-MRIs	Gadodiamide gadopentetate- dimeglumine gadobenate	Increased SI on unenhanced T1WI at posterior thalamus, substantia nigra, red nucleus, cerebellar peduncle, colliculi, DN, and GP
Ramalho et al., 2016b[15]	Studied two different groups 18 patients with previous gadodiamide and current gadobenate dimeglumine exposure 44 patients with only gadobenate dimeglumine exposure	Gadodiamide gadobenate-dimeglumine	Patients with prior gadodiamide-exposed show greater T1 SI changed compared to those without previously gadodiamide-exposed
Kang et al., 2018[16]	46 patients who had undergone >1 CE-MRIs	Gadobutrol	High SI in the DN and GP
Studies in pediatrics
Miller et al., 2015[17]	A pediatric patient who received 35 doses of linear GBCA in a 12-year period	Gadopentetate-dimeglumine	T1 hyperintensity at DN, GP, and posterior thalamus
Roberts and Holden, 2015[18]	A 13 years old girl with follow-up CE-MRI scan	Gadopentetate-dimeglumine	hyperintensity was noted within both the DN and GP bilaterally at follow-up
Roberts et al., 2016a[19]	16 patients underwent>5 consecutive CE-MRI scans	Gadopentetate-dimeglumine	T1-hyperintensity at both DN is significantly correlated to the number of prior GBCA doses
Hu et al., 2016[20]	21 patients received CE-MRI scans between 5 and 37 times; 21 controls of similar age without CE-MRI exposure	Gadopentetate-dimeglumine	Increased SI ratios in all 21 patients with GBCA exposure 18.6%±12.7% for the DN, and 12.4%±7.4% for the GP between the first and the most recent MRI scans
Flood et al., 2017[21]	46 pediatric patients who had undergone >3 CE-MRI scans; 57 age-matched GBCA-control subjects	Gadopentetate-dimeglumine	SI in the pediatric brain increases on unenhanced T1-weighted MRI with repeated exposure to linear GBCA
Ryu et al., 2018[22]	93 pediatric patients who had undergone >3 CE-MRI	Gadopentetate- gadoterate meglumine and gadoteridol	Reconfirmed that the signal intensity change is significantly and exclusively related to the use of linear agents
Autopsy studies in humans
McDonald et al., 2015[23]	13 patients with more than 4 GBCA administrations before death; control group of 10 patients with no prior CE-MRI	Gadodiamide	Gadolinium CNS structures deposition was associated with GBCA administration and was independent of patients’ age, sex, renal function or interval between GBCAs exposure and death
Kanda et al., 2015a[24]	5 patients received linear GBCAs before death; 5 patients with no history of GBCAs exposed before death	Gadopentetate-dimeglumine gadodiamide gadoteridol	Gadolinium was deposited in the brain, highest at DN and GP even in subjects without severe renal dysfunction
Murata et al., 2016[25]	5 received gadoteridol; 2 received gadobutrol; 1 received gadobenate; 1 received gadoxetate; 9 controls	Gadoteridol gadobutrol gadobenate gadoxetate	Gadolinium was found with all agents in all brain areas sampled; highest levels in GP and DN
McDonald et al., 2017[26]	5 patients underwent between 4-18 CE-MRI examinations compared to 10 patients with no history of GBCA exposure	Gadodiamide	The patient DN, pons, GP and thalamus, contained >0.1 µg of gadolinium per gram of tissue compared to those with no prior GBCAs exposure
McDonald et al., 2017[27]	3 patients underwent 4, 8, 9 CE-MRI examinations respectively	Gadodiamide	The patient DN, pons, GP and thalamus, contained >0.1 µg of gadolinium per gram of tissue

SI – Signal intensities; GBCAs – Gadolinium-based contrast agents; DN – Dentate nucleus; GP – Globus pallidus; MRI – Magnetic resonance imaging; CE-MRI – Contrast enhanced-MRI; MS – Multiple sclerosis; T1WI – T1 weighted imaging; CNS: Central nervous system