T1 Signal Measurements in Pediatric Brain: Findings after Multiple Exposures to Gadobenate Dimeglumine for Imaging of Nonneurologic Disease

Discussion

To date, no clinical signs or symptoms associated with T1 signal increases in the brain have been reported and no consequences for patient health, including neurologic function, have been identified. Nevertheless, the latest version of the American College of Radiology Manual on Contrast Media²⁷ recommends careful consideration of the clinical benefit versus the unknown potential risk of Gd deposition when deciding to perform a Gd-enhanced MR imaging study and particular attention paid to pediatric and other patients who may receive many GBCA-enhanced MR imaging studies during their lifetime. It further recommends taking into account multiple factors when selecting a GBCA, including diagnostic efficacy, relaxivity, rate of adverse reactions, dosing/concentration, and propensity to deposit in more sensitive organs such as the brain. Our findings in 34 nonneurologic pediatric patients who received between 5 and 15 administrations of low-dose (0.05 mmol/kg of body weight) gadobenate revealed no differences in T1 signal intensity in the DN, GP, pons, and thalamus relative to the SI measurements in 24 age- and weight-matched control subjects who had never been exposed to GBCA. Likewise, no significant differences in DN-pons SI ratios were noted, while just 1 of 5 blinded readers reported a significantly higher GP-thalamus SI ratio, which could be ascribed to higher T1 signal intensity in the thalamus of control subjects.

Our findings are in contrast to those of Flood et al,¹⁸ who found an increased DN-pons SI ratio in patients exposed to gadopentetate relative to GBCA-naïve control subjects (though no differences in GP-thalamus SI ratio were found) and in contrast to those of Hu et al,¹⁹ who found significantly higher T1 signal in the DN and GP of patients after serial exposure to gadopentetate than in the DN and GP of control subjects.

There are at least 2 possible reasons for the different findings. First, our patient population was different. Whereas Flood et al¹⁸ and Hu et al¹⁹ evaluated patients who had undergone multiple brain examinations, our patient cohort comprised mainly oncologic patients with no known brain abnormalities. It is thus possible that the patients evaluated by Flood et al and Hu et al were more prone to brain Gd deposition due to a more compromised blood-brain barrier. On the other hand, studies have demonstrated T1-signal increases in the DN and GP even in the presence of a seemingly intact BBB,^14,28 implying that the potential for T1-hyperintensity may be independent of the patient's clinical status and dependent solely on the amount of Gd administered. However, most of the Gd found deposited in the brain is actually in the perivascular space and has not passed the BBB,^29,30 while Gd that does appear to have crossed an intact BBB is found primarily in the neural tissue interstitium rather than in neural cells.¹⁴

Second, whereas gadobenate and gadopentetate are both ionic open-chain GBCAs, they differ fundamentally in that an aromatic substituent is present on the gadobenate molecule. On the one hand, this substituent influences the elimination profile of gadobenate, facilitating its excretion in part (typically up to 5% of the injected dose in subjects with normal renal function) via the hepatobiliary route.³¹ More pertinently, it also leads to markedly higher R1-relaxivity in vivo,²² which, in turn, leads to markedly increased SI enhancement on T1-weighted images for equivalent administered doses. A proven benefit of this higher relaxivity is that a lower gadobenate dose can be used to obtain diagnostically valid images.^23,24 In our study, the mean accumulated dose across all patients was 9.8 ± 8.33 g, administered across a mean of 7.8 ± 2.9 examinations (mean, 3.85 ± 3.14 mL of MultiHance/examination, corresponding to 1.27 ± 1.05 g of gadobenate/examination). This is considerably lower than the mean accumulated gadopentetate dose of 16.2 ± 10.1 g across a mean of 5.9 ± 2.7 examinations (mean, 2.75 g gadopentetate/examination) given by Flood et al¹⁸ and would similarly be lower than that administered by Hu et al,¹⁹ given that they injected a standard dose of 0.1 mmol/kg of gadopentetate/examination. At our institution, we routinely administer 0.05 mmol/kg of gadobenate for pediatric oncologic imaging.

An additional feature conferred by the aromatic substituent, which is invariably overlooked when simplistic comparisons are made between “linear” and macrocyclic GBCAs,^{4⇓⇓⇓⇓⇓–10,32} is improved steric hindrance and thus increased kinetic inertia. An increased steric effect conferred by a bulky substituent potentially hinders unwrapping of the ligand around the gadolinium, thereby increasing molecular stability.³³ Improved kinetic inertia due to an aromatic substituent has previously been demonstrated for gadofosveset.³⁴ Unfortunately, accurate in vivo measurements of the kinetic stability of gadobenate are currently lacking, though its thermodynamic and conditional stability constants in vitro are the highest of all open-chain GBCAs and higher also than the macrocyclic agent gadobutrol.²⁵ Further evidence of the inherent stability of gadobenate comes from the fact that this GBCA, unlike all other GBCAs except gadoterate meglumine (Dotarem; Guerbet, Aulnay-sous-Bois, France), does not contain any excess chelating agent in its formulation.²⁵ Excess chelating agent is an indirect indicator of the potential of a GBCA to release Gd; that the gadobenate formulation does not contain excess chelate implies that it does not release Gd to the same extent as other GBCAs.

Our findings are in stark contrast to those of Weberling et al,¹⁰ who found significantly increased DN-pons and DN-CSF SI ratios after serial exposures of gadobenate to adults. However, several factors should be borne in mind when evaluating the results of Weberling et al. First, the patients evaluated were only required to have had a minimum of 5 consecutive gadobenate-enhanced MR imaging scans; each patient's first included scan was not necessarily the first scan the patient received, and prior scans with other GBCAs might have been performed. The likelihood that patients might have had prior MR imaging exams with other GBCAs is clearly a major confounding factor. Ramalho et al¹² showed that significant T1 hyperintensity in deep brain nuclei occurred after the use of gadobenate in patients who had received prior administration of gadodiamide (Omniscan; GE Healthcare, Piscataway, New Jersey), but not in patients who had not previously received gadodiamide. An earlier report by Ramalho et al¹¹ demonstrated significant SI increases in the DN and GP of patients who had received gadodiamide but not in patients who had received gadobenate. The lack of adequate patient screening by Weberling et al¹⁰ means that possible potentiating effects of prior exposure to other GBCAs could not be excluded.

Second, each patient evaluated by Weberling et al¹⁰ received a standardized volume of 15 or 20 mL of gadobenate per examination irrespective of body weight, resulting in a mean accumulated volume of 136.9 ± 57.6 mL (ie, a mean accumulated dose of 45.72 g of gadobenate) between the first and last MR imaging examinations. Given that an approved gadobenate dose for all indications other than the liver, kidneys, urinary tract, and adrenal glands is 0.1 mmol/kg of body weight,²⁶ which corresponds to 15 mL for a 75-kg patient, any patient below 75 kg in weight would have received more than the approved dose (ie, more than the approved amount of Gd). Third, all except 1 of the patients evaluated by Weberling et al had brain metastases from melanoma, with many undergoing radiation therapy. These patients would certainly have had a more severely compromised BBB, potentially allowing easier GBCA access to deep brain nuclei.

Weberling et al¹⁰ ascribed their observed SI increases to Gd retention, speculating that their findings reflect the specific potential of gadobenate to release Gd. In drawing parallels with the postulated causative role of GBCAs in nephrogenic systemic fibrosis (NSF), they noted that gadobenate is classified as being of intermediate risk for NSF by the European Medicines Agency³⁵; and in referring to 1 in vitro determination of kinetic stability conducted by a competitor to the manufacturer of gadobenate,³⁶ they suggested that the potential for Gd release is similar for gadobenate and gadopentetate. Unfortunately, in vitro determinations of kinetic stability are inherently limited in that they cannot replicate normal physiologic conditions in vivo and cannot account for differing and unique routes of elimination among GBCAs. Although Weberling et al¹⁰ acknowledged that no unconfounded cases of NSF have been reported for gadobenate,³⁷ they failed to point out that other relevant regulatory authorities, including the US Food and Drug Administration, classify gadobenate as having a low risk of NSF.^38,39 In this regard, most (73%) of the unconfounded published NSF cases were reported in the United States,⁴⁰ and at the height of the NSF crisis (2006–2010), just 1 macrocyclic GBCA (gadoteridol, ProHance; Bracco Diagnostics) had FDA approval for commercial use. Gadobutrol (Gadavist; Bayer Healthcare) and gadoterate (Guerbet) were approved in 2011 and 2013, respectively. The other approved GBCAs besides gadobenate were gadodiamide (GE Healthcare), gadoversetamide (OptiMARK; Covidien), and gadopentetate (Bayer Healthcare), which were avoided and subsequently contraindicated in patients with severe renal impairment,³⁸ leaving only gadobenate as an approved open-chain GBCA for routine applications in this population.

If, as is widely accepted, NSF occurs because of Gd release from the chelating molecule,³⁵ then at least 1 unconfounded case might have been expected for gadobenate if, as postulated by Weberling et al,¹⁰ Gd is released in vivo to an extent similar to that seen with gadopentetate. That no unconfounded cases have been reported despite exhaustive investigation^41⇓–43 suggests that Gd is not released from gadobenate to the same extent and that any observed T1 hyperintensity reflects retention of the intact molecule. Roberts et al⁴⁴ recently reported high levels of Gd in the skin of a patient who underwent 61 enhanced brain examinations with a variety of GBCAs and that speciation analysis revealed intact gadobenate.

Further studies are required to determine whether T1 hyperintensity is seen in some patients after serial gadobenate exposure, and if so, whether this reflects accumulation of intact gadobenate or released Gd bound to macromolecules (eg, neuromelanin). In this regard, it is possible that Gd released from less stable GBCAs binds to macromolecules and that the observed T1 hyperintensity reflects elevated T1-signal due to slowing of the molecular tumbling rate of these Gd-macromolecule complexes.³⁰ This hypothesis might explain why elevated T1 signal is observed with less stable GBCAs despite the very small Gd concentrations shown to be retained²⁰ and, conceivably, why detectable high signal is less evident with more stable GBCAs if these are retained as fully intact molecules rather than as Gd-macromolecular complexes.⁴⁵ Of note, however, is the study by Stojanov¹³ and a recent study in pediatric subjects by Rossi Espagnet et al.⁴⁶ that demonstrate quantifiable T1 signal increases after multiple exposures to the macrocyclic GBCAs gadobutrol and gadoterate, respectively.

Also worthy of study is the possible differential impact of GBCA R1-relaxivity on T1 hyperintensity if GBCAs are retained as intact molecules; it is likely that retained GBCAs that have low R1-relaxivity may be less detectable than retained intact GBCAs that have higher R1-relaxivity. Finally, T1 signal increases are merely suggestive of Gd retention, and T1 hyperintensity might alternatively reflect various disease-related processes.^47⇓–49 While imaging studies can be considered, at best, an indirect second-level marker of Gd deposition, a true picture can only come from direct tissue analysis. In this regard, studies have demonstrated measurable Gd not only in the DN and GP but also in other brain areas and body organs.^14,20,28 Most important, Murata et al²⁰ have shown that deposition occurs with both linear and macrocyclic GBCAs and that it is up to 23 times higher in organs such as bone than in the brain.

Despite excellent interreader agreement regarding the reproducibility of SI measurements and despite the absence of significant differences in SI values between gadobenate-exposed and GBCA-naïve control subjects across any of the 4 evaluated brain regions, a significant difference in the GP-thalamus SI ratio was nevertheless still observed in 1 of the 5 blinded assessments. Although this can be explained by higher T1 signal in the thalamus of control subjects, it highlights the potential impact of even minimal differences in SI measurements on study interpretation. This, in turn, points to the importance of multiple readers when performing quantitative evaluations and to the dangers of drawing conclusions based on evaluations performed by just 1 or 2 readers, particularly if such readers are not blinded to information regarding the images under evaluation. Accurate placing of ROIs for quantitative assessment is a highly subjective procedure, which is susceptible to considerable interreader variation.

Our study has some limitations. First, this was a single-center study. Second, because we assessed nonneurologic patients who had not previously undergone MR imaging of the brain, it was not possible to compare unenhanced T1-weighted images after multiple gadobenate administrations with baseline unenhanced images acquired before the first gadobenate administration. However, the lack of significant SI differences between gadobenate-exposed and GBCA-naïve control subjects suggests that no differences would have been seen. Third, we determined DN-pons and GP-thalamus SI ratios despite Gd retention being observed in both the pons and thalamus.^14,20 However, the T1 signal changes in these brain areas are much lower than in the DN and GP, and these ratios are commonly calculated parameters.^{1⇓⇓–4,8⇓⇓⇓⇓–13,16⇓–18} Finally, we did not normalize the SI values of the DN and GP against the SI of the CSF to account for possible intra- and intersequence signal-intensity differences, differences between MR units, and magnetic field inhomogeneity as described by McDonald et al.¹⁴ SI normalization might be appropriate for future studies.