LAUSR

M agnetic resonance (MR) examinations performed with gadolinium-based contrast agents (GBCAs) are widely used clinically in the pediatric population and provide essential information to guide the diagnosis and treatment of childhood diseases throughout the body. Several GBCAs are available for clinical use in children, and 3 GBCAs have approval in the United States for use in children less than 2 years. Gadolinium-based contrast agents are classified according to their chemical structure as either linear or macrocyclic with the macrocyclic structure achieving higher stability than the open chain linear agents. Gadolinium-based contrast agents have been considered extremely safe drugs, and it is standard of care to administer GBCAs to children of all ages when clinically indicated, including preterm neonates. Recently, however, it has been shown that detectable amounts of gadolinium remain in the body and accumulate in sensitive tissues such as the brain after repeated GBCA administrations in patients despite normal renal function. Hyperintense signal within the dentate nucleus and globus pallidus on unenhanced T1-weighted images has been shown to be a marker for gadolinium accumulation in the brain and occurs in both adults and children. Gadolinium has been detected in human brain tissue after both linear and macrocyclic agents but at much lower levels in patients who received macrocyclic GBCAs. Human autopsy studies of adult decedents have demonstrated the presence of retained gadolinium within endothelial walls, neural interstitium, and nuclei of neurons. To date, no definite evidence of GBCA-resultant neural tissue injury has been observed on conventional histopathology, but caution should be exercised when extrapolating the results of adult toxicity studies to pediatric populations. Only 2 postmortem pediatric case reports have been published describing gadolinium retention in the brains of 4 pediatric patients ranging in age from 8 to 17 years. On histology, gliosis was found within the dentate tissues of 2 of these patients; however, it was unclear whether the pathologic changes were the result of prior radiation therapy or associated with the presence of gadolinium. Currently, the relatively small number of studies has therefore not adequately addressed the question of pediatric GBCA retention–potentiated histopathological neurotoxicity. Gadolinium is also known to accumulate in human bone tissue and can be detected several years after the last GBCA administration. The bone samples in these studies, however, were from older adults undergoing hip replacement surgery and did not include children. As in the brain, gadolinium retention in bone is dependent on the class of agent used. For example, in one study, gadolinium levels were found to be approximately 4 times greater after the administration of a nonionic linear GBCA than a macrocyclic GBCA; however, this difference may have been underestimated due to the timing of sample collection. Also in adult patients, the retention of gadolinium in bone has been shown to be 23 times higher than in the brain. Currently, there are no human data available concerning gadolinium deposition in pediatric bone tissue. This is of concern, because it is unknown if the administration of cumulative doses of gadolinium during active bone formation could result in even higher levels of gadolinium deposition in children than in older adults. Any potential risk to active hematopoietic marrow in children is also unknown. With so much unknown, preclinical animal studies provide crucial well-controlled models for understanding the time course and variability of deposition by differing chemical forms of gadolinium contrast agents. Gadolinium retention has been described in animals with normal renal function, and a recent study has demonstrated up to 75% of a linear agent present in the brains of rats immediately after the last injected dose was still present as soluble gadolinium bound to macromolecules 1 year later. In contrast, rapid time-dependent washout of intact GBCA to background levels was described in animals receiving a macrocyclic agent. Understanding the pharmacodynamics of various clinically used GBCAs in the pediatric population is especially important considering the life-time of potential exposure and