Intrathecal Use of Gadobutrol for Glymphatic MR Imaging: Prospective Safety Study of 100 Patients

Abstract

Background and purpose: Intrathecal contrast-enhanced glymphatic MR imaging has shown promise in assessing glymphatic function in patients with dementia. The purpose of this study was to determine the safety profile and feasibility of this new MR imaging technique.

Materials and methods: A prospective safety and feasibility study was performed in 100 consecutive patients (58 women and 42 men, 51 ± 19 years of age) undergoing glymphatic MR imaging from September 2015 to August 2018. Short- and long-term serious and nonserious adverse events were registered clinically and by interview after intrathecal administration of 0.5 mL of gadobutrol (1.0 mmol/mL) along with 3 mL of iodixanol (270 mg I/mL). Adverse events are presented as numbers and percentages.

Results: One serious adverse event (anaphylaxis) occurred in a patient with known allergy to iodine-containing contrast agents (1%). The main nonserious adverse events during the first 1-3 days after contrast injection included severe headache (28%) and severe nausea (34%), though the frequency depended heavily on the diagnosis. After 4 weeks, adverse events had resolved.

Conclusions: Intrathecal administration of gadobutrol in conjunction with iodixanol for glymphatic MR imaging is safe and feasible. We cannot conclude whether short-duration symptoms such as headache and nausea were caused by gadobutrol, iodixanol, the lumbar puncture, or the diagnosis. The safety profile closely resembles that of iodixanol alone.

Fig 1.

gMRI in a subject with iNPH. Intrathecal gadobutrol (0.05 mmol) used as a CSF tracer, followed by MR imaging acquisitions after 2, 4, 6, and 24 hours, shows enrichment of the CSF tracer as a percentage change in the T1 signal unit ratio. The color scale shows a contrast agent–dependent percentage increase in the T1 signal unit ratio (for more detailed description see Ringstad et al). Note that contrast enhancement of the brain occurred in a centripetal pattern and primarily in regions of the brain adjacent to large artery trunks at the surface—that is, the anterior, middle, and posterior cerebral arteries. The periventricular tracer enhancement is due to reflux of tracer into the ventricular system, which is a typical feature of iNPH.

Fig 2.

Entry of gadobutrol into the CSF within the intracranial compartment at consecutive MR imaging of a patient with a pineal gland cyst (A) and iNPH (B). Intrathecal administration of 0.5 mL (1.0 mmol/mL) of gadobutrol at the lower lumbar level was preceded by unenhanced, T1-weighted MR imaging (time point zero). After the correct needle position had been verified at fluoroscopy by injection of 3 mL of iohexanol (270 mg I/mL), the patient was transported in the supine position to the MR imaging suite next door, and acquisition of identical, consecutive T1 scans was initiated immediately and performed continuously within the first hour. Typically, the contrast agent had reached the cisterna magna at the first postcontrast scan obtained after approximately 10 minutes (A, thick arrow). In some patients, however, enhancement occurred much later, as in B, where slight enhancement was first depicted at 1 hour (thin arrow). At 6-hour scans, gadobutrol is distributed widely in the CSF of both patients, but less prominently in B, where ventricular reflux can also be noted.

Fig 3.

gMRI shown as standardized T1 acquisitions before and 24 and 48 hours after intrathecal gadobutrol in a subject with iNPH, including midsagittal, midaxial, and midcoronal images. In iNPH, gadobutrol clearance from the CSF is delayed compared with reference patients at 24 and 48 hours, respectively. Other typical features of iNPH are early ventricular reflux and subsequent periventricular enhancement of contrast agent, typically most prominent at 24 hours.

Fig 4.

The time from intrathecal administration of gadobutrol until the first enhancement of the contrast agent within subarachnoid space of the foramen magnum (spinal transit time) for the 100 patients included in the study. The mean ± SD spinal transit time was 20 ± 23 minutes.