Brain DSC MR Perfusion in Children: A Clinical Feasibility Study Using Different Technical Standards of Contrast Administration

Discussion

The diagnosis of pediatric brain tumors is almost always based on patient age, tumor location, and conventional neuroimaging findings. However, additional goals for brain MR imaging for pediatric brain tumors should include differentiating specific tumor types, grading tumors, distinguishing viable tumor from necrotic tissue, guiding stereotactic biopsy, and determining treatment responses. Perfusion MR imaging provides the degree of neovascularity/tumor angiogenesis and is extremely useful for tumor characterization, grading, and prognosis.

There are currently 3 available techniques for perfusion MR imaging: dynamic susceptibility contrast imaging, dynamic contrast-enhanced imaging, and arterial spin-labeling. Arterial spin-labeling is particularly easy, safe, and suitable for children due to the lack of exogenous contrast agent administration, but this technique is still gaining clinical acceptance. Both DSC and dynamic contrast-enhanced imaging need the same exogenous contrast agent (GBCA), with a universally accepted role in the characterization of brain tumors and mandatory administration in such clinicoradiologic scenarios, independent of patient age. A clear advantage of arterial spin-labeling is that CBF quantification is not affected by T1 and T2 leakage effects with blood-brain barrier disruption, but arterial spin-labeling can currently provide values of only CBF (relative and absolute), which showed a good correlation with DSC CBV. On the other hand, DSC imaging sets also contain information regarding the flow and permeability properties of the tumor microvascular system, and DSC provides several perfusion parameters, reported as useful in the assessment of pediatric brain tumors: percentage of signal recovery, pattern of contrast leakage, and time-to-maximum.^8,9

DSC imaging is currently considered the standard perfusion MR imaging method for brain tumors and is far more commonly used in the clinical setting because of its relatively short imaging time and the wider availability of image-processing tools. However, DSC imaging is technically more challenging in children compared with adult patients because it requires high-flow contrast injection, a compact bolus, proper venous access (18–20 ga), and patient immobility according to the American Society of Functional Neuroradiology recommendations.¹⁰ Few studies report the use of DSC imaging in pediatric patients to date and often include confounding inclusion/exclusion criteria. Ho et al^8,11 evaluated the utility of relative CBV data from DSC imaging for grading pediatric primary brain tumors but did not provide detailed information regarding injection rates or patient age. Our study is the first to systematically determine the feasibility, safety, and quality of DSC MR perfusion imaging in children, using a custom child administration of a standard dose of gadolinium (0.1 mmol/kg dose of gadobutrol; Gadovist). We first demonstrated the technical feasibility of DSC-PWI in children and considered that the technique remains within the estimated cost, does not need additional or particular tools, and will be profitable in terms of clinical information. We carefully analyzed the safety of MR perfusion examinations in children, and all were well-tolerated and without adverse effects, notably with respect to the intravenous administration of contrast material performed with a power injector and various flow rates. We accurately customized the contrast medium administration for each patient, because we know from experience that the size of the child affects venous access and the ability to meet the standard adult requirements. Our safety standards required that 1 member of the MR imaging team (neuroradiologist, nurse, anesthesiologist) obtain peripheral venous access or check the pre-existing venous access site when patients and their parents arrive at the MR imaging unit. The key step was the accurate determination of the best venous access, which specified the appropriate needle gauge and the subsequent contrast medium flow rate. The peripheral IV catheters were always checked before examination by applying 5–10 mL of saline solution and were evaluated for blood return, and the connective tubing was attached to 1 of the power injectors. A new peripheral venous access site was inserted if the IV catheter could not be adequately flushed with saline or if the patient experienced pain at the injection site when not sedated. All aspects of the examination were explained to the parents of the children before the study, including the use of venous access to inject a small volume of contrast medium, and this information was well-received by parents. We strongly believe that our safety standards, customized to each patient, allow DSC studies to be performed safely, with no extravasation or other local reactions/adverse effects recorded.

Finally, we analyzed and reported the DSC perfusion quality. We intentionally chose gadobutrol for its high relaxivity and high concentration. Values obtained for FWHM with gadobutrol were lower than those obtained with other less concentrated contrast agents,⁷ and although it has been reported that the reduced gadobutrol injection time did not show a positive effect on the bolus geometry in adults,¹² we speculated that a reduced bolus volume and consequently reduced injection rate may be advantageous for the bolus profile in our pediatric population. The comparison or enlargement of our data with those of future studies is now possible and in line with these suggestions.

We achieved high-quality CBV maps and signal intensity–time curves in all patients, even with very low-flow injection rates such as 1–2 mL/s. A flow rate of 1 mL/s was effective in achieving good-quality maps and curves (respectively evaluated with the maximum score and rated as good or excellent by the 2 readers) in 3 patients between 5 and 7 months of age, with a mean PSD value (31.6%) that is considered appropriate for routine clinical studies⁷ and a mean FWHM only slightly higher than 7 seconds, but similar to others obtained with faster flow rates in our population. In addition, neither the PSD nor FWHM showed statistically significant differences for gray and white matter between the groups' high- and low-flow rates. This means that even performing DSC-PWI at a lower flow rate we achieved good perfusion data. We demonstrated that a compact contrast bolus is achievable even using lower flow rates, particularly for young-age and low-weight children, resulting in a good or excellent quality of the curve and a high PSD. A univocal explanation for the FWHM of >7 seconds in 20 patients was not fully identified, but the relatively higher FWHM did not negatively affect the image quality in these 20 patients, and only 1 (a patient with a flow rate of 1 mL/s) had a PSD slightly lower than the accepted threshold of 30%.

As expected, the PSD was higher for gray matter than for white matter, whereas the FWHM was lower.⁷

Only the FWHM of the lenticular nuclei correlated with age, weight, and, consequently, the amount of contrast medium. The reasons for the similar PSDs obtained despite different injection rates and the higher FWHM obtained with increasing age, weight, and contrast amount remain to be clarified. Multiple factors may compete with the contrast flow velocity in children and exert a greater power to narrow the contrast bolus. Faster heart rates, faster circulation, shorter distance to reach the brain, a smaller capillary bed of the lung, and smaller perfusion cross-sectional area in juvenile brains may reduce the general broadening of the bolus, leading to a bolus geometry similar to that obtained with the higher flow rates and volumes of contrast media in adults.² It is also well-accepted that cerebral blood flow tends to decrease throughout childhood, reaching adult levels by the late teens.¹³ It should be assumed that the width of the curve (FWHM) is more influenced by the increase in the bolus distribution in the vascular tree than the PSD, with other parameters such as flow velocity being equal. In our population, the result of the highest PSD among the group with flow rates of 3 mL/s in gray matter (Fig 2B) is not completely clear; a larger population is needed to perform stronger statistical analyses among age-related groups. In adults, sex differences in cerebral perfusion have been reported, with women having higher CBF values than men, but the factors modulating this sex difference in perfusion remain unclear. In our population, girls showed a lower FWHM of gray matter in the 0- to 6-year-old group, but it was higher in the 13- to 16-year-old group (Fig 3). Differences in hematocrit and steroid hormone levels have been brought into play to explain the sex difference in adult cerebral perfusion,^14,15 but more studies on pediatric brain perfusion are warranted to define a sex difference in brain hemodynamics and to better understand the biologic causes.

Sedation was always used in children younger than 6 years of age, and while some anesthetic agents used in pediatric anesthesia decrease CBF indirectly,¹⁶ no cases of low-quality DSC perfusion studies were recorded in our population. Moreover, the use of DSC MR perfusion does not significantly extend the duration of sedation because it lasts approximately 1–1.30 minutes. Ultimately, our effort was to determine that DSC is feasible in pediatric patients; thus, when the use of gadolinium is deemed clinically necessary, the gadolinium bolus can be used to obtain DSC perfusion with administration parameters suitable for pediatric populations. Gadolinium deposition in the brain after the use of gadolinium-based contrast agents has been documented extensively in the literature.^17⇓–19 Brain deposition is most noticeable with linear agents in both adults and children, and at present, the GBCA gadobutrol seems less likely to deposit within the brain in comparison with other linear and macrocyclic GBCAs.¹⁸ Bjørnerud et al²⁰ reported, in an adult population, an increased T1 signal intensity in the dentate nucleus after a very high number (>30) of administrations of gadobutrol, but in pediatric patients, this agent was not associated with the MR imaging evidence of brain deposition.²¹ However, while gadobutrol may be less likely to deposit within the brain in comparison with other GBCAs, in our study, we chose this contrast agent due only to its characteristics of high relaxivity and high concentration, because in early 2014, when we were planning this study, there was not yet scientific evidence of gadolinium deposition in the brain. Finally, to date, no detrimental impact of these depositions has been identified.

The primary limitation of the study is the small population, which does not allow the identification of factors that can influence the quality of perfusion images more than others. Therefore, DSC should be performed in a larger pediatric population to clarify the mechanisms behind the similar bolus geometry despite the different injection flow rates in children with respect to adults. Another limitation is the low number of perfusion studies obtained at 3T, which does not allow comparisons of the quality of perfusion at 1.5T and 3T. However, considering the high quality of perfusion that we achieved at 1.5T and that, in general, 3T provides a greater SNR,²² we can speculate that pediatric brain DSC perfusion at low-flow rates may benefit from higher field strengths.

With such a wide age range of patients, to homogenize our data and have similar acquisitions, we decided not to use a preload because the precise administration of a quarter dose of 1 mol of contrast for children weighing less than 10 kg meant being able to administer less than 0.2 mL. In adult populations, to reduce the so called “leakage effect,” we usually use a preload of one-quarter of the total dose, about 5–10 minutes before the DSC acquisition as well as postprocessing leakage-correction algorithms. Benefits of the use of preload administration are particularly evident in the presence of BBB disruption, which may cause an underestimation of the relative CBV,²³ but in our population, quantitative data of DSC were measured in normal-appearing gray and white matter, where there was no evidence of alterations of the BBB. One of the limits of our study is the use of different flip angles, due to the different vendors and magnetic fields, while we used the same postprocessing leakage-correction algorithm.