Off-label intrathecal use of gadobutrol: safety study and comparison of administration protocols

Abstract

Purpose: Magnetic resonance imaging (MRI) contrast agents have been used off-label for diagnosis of cerebrospinal fluid (CSF) leaks and lately also for assessment of the glymphatic system and meningeal lymphatic drainage. The purpose of this study was to further evaluate the short- and long-term safety profile of intrathecal MRI contrast agents.

Methods: In this prospective study, we compared the safety profile of different administration protocols of intrathecal gadobutrol (Gadovist^TM; 1.0 mmol/ml). Gadobutrol was administered intrathecal in a dose of 0.5 mmol, with or without iodixanol (Visipaque^TM 270 mg I/ml; 3 ml). In addition, a subgroup was given intrathecal gadobutrol in a dose of 0.25 mmol. Adverse events were assessed at 1 to 3 days, 4 weeks, and after 12 months.

Results: Among the 149 patients, no serious adverse events were seen in patients without history of prior adverse events. The combination of gadobutrol with iodixanol did not increase the occurrence of non-serious adverse events after days 1-3. Intrathecal gadobutrol in a dose of 0.25 mmol caused less severity of nausea, as compared with the dose of 0.5 mmol. The clinical diagnosis was the major determinant for occurrence of non-serious adverse events after intrathecal gadobutrol.

Conclusion: This prospective study showed that intrathecal administration of gadobutrol in a dose of 0.5 mmol is safe. Non-serious adverse events were to a lesser degree affected by the administration protocols, though preliminary data are given that side effects of intrathecal gadobutrol are dose-dependent.

Keywords: Contrast agents; Gadobutrol; Glymphatic function; Iodixanol; Magnetic resonance imaging; Safety.

Fig. 1

Intrathecal injection of gadobutrol in a dose of (a) 0.25 mmol (0.25 ml of 1.0 mmol/ml) or (b) 0.5 mmol (0.50 ml of 1.0 mmol/ml) at the lower lumbar level. Entry of gadobutrol in CSF within the intracranial compartment was preceded by unenhanced T1-weighted MRI (time point “Pre”), and acquisition of identical consecutive T1 scans was initiated immediately and repeated at different time points. Image window/level is adjusted to optimize qualitative illustration of CSF contrast enhancement

Fig. 2

There was no significant difference between patient groups regarding time from intrathecal administration of gadobutrol until first enhancement of the contrast agent within the subarachnoid space of the foramen magnum (spinal transit time). For the entire group of 149 individuals, the mean ± stdev spinal transit time was 22 ± 34 min. The tentative diagnoses were as follows: iNPH, idiopathic normal pressure hydrocephalus; SIH, spontaneous intracranial hypotension; AC, arachnoid cyst; PC, pineal cyst; IIH, idiopathic intracranial hypertension; cHC, communicating hydrocephalus; and ncHC, non-communicating hydrocephalus

Fig. 3

CSF tracer enrichment in cisterna magna depending on dose of CSF tracer (gadobutrol), measured as percentage change in normalized T1 signals after intrathecal injection of gadobutrol in doses of 0.5 mmol (protocols #1–2; blue line) or 0.25 mmol (protocol #3; red line). The first time point is after 10 min. The CSF tracer level was significantly different after 3 h (P < 0.001), 6 h (P = 0.001), and 48 h (P = 0.047; independent samples t test).