Age-related changes in the distribution of intravenously administered gadolinium-based contrast agents leaked into the cerebrospinal fluid in patients with suspected endolymphatic hydrops.

PURPOSE: The purpose of this retrospective study was to investigate the relationship between age and leakage of intravenously administered gadolinium-based contrast agents (GBCAs) into the cerebrospinal fluid (CSF) by volumetric segmentation of the whole-cranium CSF. MATERIALS AND METHODS: In 30 patients clinically diagnosed with suspected endolymphatic hydrops, the three-dimensional real inversion recovery (3D-real IR) images were obtained at pre- and 4 h post-intravenous administration of a single dose of GBCA. The volume of interest was set on the whole-cranium CSF in the 3D-real IR image. The signal intensity (SI)-increase of the ventricular CSF and the extra-ventricular CSF at 4 h post-administration of GBCA compared to pre-administration was measured. The relationship between the age of the patient and the SI-increase was evaluated. RESULTS: A correlation between age and the SI-increase was observed in the whole-cranium CSF. The correlation coefficient between age and the SI-increase in the ventricular CSF was higher than that in the extra-ventricular CSF. CONCLUSION: An age-related leakage of the intravenously administered GBCAs was found in the whole-brain CSF. The age-related change in the distribution of the GBCA leakage was more prominent in the ventricular CSF than in the extra-ventricular CSF.

Optimal Detection of Subtle Gadolinium Leakage in CSF with Heavily T2-Weighted Fluid-Attenuated Inversion Recovery Imaging.

Pericortical enhancement on postcontrast FLAIR images is a marker for subtle leptomeningeal blood-brain barrier leakage. We explored the optimal FLAIR sequence parameters for the detection of low gadolinium concentrations within the CSF. On the basis of phantom experiments and human in vivo data, we showed that detection of subtle pericortical enhancement can be facilitated by using a relatively long TE. Future studies should choose their FLAIR sequence parameters carefully when assessing pericortical enhancement due to subtle blood-brain barrier leakage.

Accumulation of Gadolinium in Human Cerebrospinal Fluid after Gadobutrol-enhanced MR Imaging: A Prospective Observational Cohort Study.

Purpose To determine whether gadolinium accumulates within cerebrospinal fluid (CSF) in patients recently exposed to the macrocyclic agent gadobutrol and identify factors that may affect this accumulation. Materials and Methods In this prospective observational cohort study, gadolinium was quantified by using inductively coupled plasma mass spectrometry of CSF samples from patients who underwent gadobutrol-enhanced magnetic resonance (MR) imaging followed by lumbar puncture within 30 days (gadobutrol group) or patients who underwent lumbar puncture without history of gadolinium-enhanced MR imaging (control group). CSF total protein level of 35 mg/dL or lower was used as a surrogate marker of an intact blood-brain barrier (BBB). Associations between gadolinium CSF concentration and patient characteristics were examined by using log (e)-linear regression models. Results A total of 82 patients (68 in gadobutrol group, 14 in control group; 42 male and 40 female patients; median age, 47 years [interquartile range, 25-65 years]) were included in this study. Gadolinium was detected in the CSF of all 68 patients in the gadobutrol group (100% [95% confidence interval: 94.7, 100]; range, 0.2-1494 ng/mL). CSF total protein level higher than 35 mg/dL and patient age of at least 18 years were associated with higher gadolinium concentrations (estimate: 1.1, with standard error [SE] of 0.26 [P < .001] and 0.91, with SE of 0.37 [P = .02], respectively). Conclusion Intravenous administration of the macrocyclic agent gadobutrol results in gadolinium accumulation within the CSF, even in the setting of normal renal function and no BBB dysfunction.

Gadolinium-based Contrast Media, Cerebrospinal Fluid and the Glymphatic System: Possible Mechanisms for the Deposition of Gadolinium in the Brain.

After Kanda's first report in 2014 on gadolinium (Gd) deposition in brain tissue, a considerable number of studies have investigated the explanation for the observation. Gd deposition in brain tissue after repeated administration of gadolinium-based contrast medium (GBCM) has been histologically proven, and chelate stability has been shown to affect the deposition. However, the mechanism for this deposition has not been fully elucidated. Recently, a hypothesis was introduced that involves the 'glymphatic system', which is a coined word that combines 'gl' for glia cell and 'lymphatic' system. According to this hypothesis, the perivascular space functions as a conduit for cerebrospinal fluid to flow into the brain parenchyma. The perivascular space around the arteries allows cerebrospinal fluid to enter the interstitial space of the brain tissue through water channels controlled by aquaporin 4. The cerebrospinal fluid entering the interstitial space clears waste proteins from the tissue. It then flows into the perivascular space around the vein and is discharged outside the brain. In addition to the hypothesis regarding the glymphatic system, some reports have described that after GBCM administration, some of the GBCM distributes through systemic blood circulation and remains in other compartments including the cerebrospinal fluid. It is thought that the GBCM distributed into the cerebrospinal fluid cavity via the glymphatic system may remain in brain tissue for a longer duration compared to the GBCM in systemic circulation. Glymphatic system may of course act as a clearance system for GBCM from brain tissue. Based on these findings, the mechanism for Gd deposition in the brain will be discussed in this review. The authors speculate that the glymphatic system may be the major contributory factor to the deposition and clearance of gadolinium in brain tissue.

Magnetic resonance cisternogram with intrathecal gadolinium with delayed imaging for difficult to diagnose cerebrospinal fluid leaks of anterior skull base.

BACKGROUND: Workup of cerebrospinal fluid (CSF) leaks can be challenging. Patients with intermittent or infrequent clear rhinorrhea that cannot be collected, those with questionable or multiple skull-base (SB) defects on imaging, and those with previous SB surgery can present diagnostic dilemmas. In this patient population, radiologic studies that allow repeat imaging over hours to days can increase the diagnostic yield. We report our experience with magnetic resonance cisternogram with intrathecal gadolinium (MRCgGd) in this patient population. METHODS: This study was a retrospective review of patients who underwent MRCgGd for workup of suspected CSF leaks at a tertiary care academic center. RESULTS: Over the past 3 years, 11 patients (10 females; mean age 50 years) underwent MRCgGd. Seven patients had suspected spontaneous CSF leaks from idiopathic intracranial hypertension and 2 had postsurgical defects. All patients had previous imaging that was indeterminate in localizing the site of the leak. Only 3 patients had positive beta-2 transferrin studies, all with multiple potential leak sites. MRCgGd confirmed the absence of leaks at 4 previously repaired SB defects, identified spinal canal leaks but no SB leaks in 2 patients (1 of whom had a nonleaking SB defect), and identified 5 patients with one or more SB leaks. Repeat imaging, from 30 minutes to 20 hours, was beneficial in identifying 4 leaks not confirmed in the immediate imaging, and ruling out leaks in 5 cases, therefore guiding further treatment. No complications occurred. CONCLUSION: MRCgGd is a useful diagnostic test in the workup of patients with difficult CSF leaks, with delayed imaging providing valuable diagnostic information.

Serial scans in healthy volunteers following intravenous administration of gadoteridol: time course of contrast enhancement in various cranial fluid spaces.

PURPOSE: Heavily T2-weighted, 3-dimensional, fluid-attenuated inversion recovery (hT2W-3D-FLAIR) imaging has been reported to detect low concentrations of gadolinium-based contrast media (GBCM) in the anterior eye segment (AES), subarachnoid space (SAS), and labyrinthine perilymph as well as in the cerebrospinal fluid (CSF) of the internal auditory canal (IAC) 4 hours after intravenous administration of a single dose (IV-SD-GBCM) in patients with inner ear disorders. To elucidate the time course of contrast enhancement in healthy volunteers, we obtained hT2W-3D-FLAIR serially after IV-SD-GBCM. MATERIALS AND METHODS: We obtained hT2W-3D-FLAIR before and 0.5, 1.5, 3, 4.5 and 6 hours after IV-SD-GBCM in 6 healthy volunteers and measured signal intensity of the AES, SAS surrounding the optic nerve (SAS-ON), SAS in Meckel's cave (SAS-MC), pontine parenchyma, CSF in the IAC (CSF-IAC), CSF in the ambient cistern (CSF-AC), CSF in the lateral ventricles (CSF-LV), perilymph (PL), and endolymph (EL) in the labyrinth. We then compared averaged values among all time points using analysis of variance (ANOVA). RESULTS: After IV-SD-GBCM, we observed no change in signal intensity in the pontine parenchyma, CSF-LV, or EL and significant enhancement in all other structures. Maximum enhancement was most frequent at 4.5 hours after IV-SD-GBCM in the SAS-ON and PL, at 1.5 hours in the AES and SAS-MC, and at 3 hours in the CSF-IAC and CSF-AC. CONCLUSIONS: Contrast enhancement can be detected by hT2W-3D-FLAIR in the AES, SAS-ON, SAS-MC, PL, CSF-IAC, and CSF-AC in healthy volunteers after IV-SD-GBCM. Timing of maximum enhancement differed among locations. These data might serve as basic knowledge for future clinical research.

Neurosarcoidosis: correlation of cerebrospinal fluid findings with diffuse leptomeningeal gadolinium enhancement on MRI and clinical disease activity.

BACKGROUND: Cerebrospinal fluid (CSF) examination is considered important in the diagnosis of neurosarcoidosis, however, data on whether and how CSF parameters may be related to MRI findings and clinical disease activity of patients with neurosarcoidosis are scarce. OBJECTIVE: To correlate CSF findings in patients with neurosarcoidosis with MRI findings and clinical disease activity. MATERIAL AND METHODS: Results of 51 comprehensive CSF examinations of 25 patients with probable or definite neurosarcoidosis according to the Zajicek-criteria were analyzed retrospectively. RESULTS: Patients with diffuse leptomeningeal gadolinium enhancement on MRI had significantly higher cell counts (≥50 cells/µl in 80%), total protein (≥200 mg/dl in 80%), CSF/serum albumin quotients (Q(Alb), ≥30 in 80%), and lactate (≥30 mg/dl in 70%), but significantly lower glucose levels (≤40 mg/dl in 67%) than patients without leptomeningeal enhancement. Irrespective of MRI findings, activated lymphocytes and plasma cells were detected in the initial CSF examination in 60% and 47% of patients, and an intrathecal synthesis of IgG, IgA, and IgM in 22%, 29%, and 22%. Patients with clinically active disease had significantly higher CSF cell counts, total protein, Q(Alb), and lactate, but significantly lower glucose levels than patients with stable disease. CONCLUSION: CSF abnormalities in neurosarcoidosis are most pronounced in patients with diffuse leptomeningeal enhancement on MRI. CSF analyses may thus aid in the distinction of different radiographic and pathologic manifestations of neurosarcoidosis. Furthermore, CSF examinations may allow monitoring disease activity in patients with neurosarcoidosis.

The hyperintense acute reperfusion marker on fluid-attenuated inversion recovery magnetic resonance imaging is caused by gadolinium in the cerebrospinal fluid.

BACKGROUND AND PURPOSE: The hyperintense acute reperfusion marker (HARM) on fluid-attenuated inversion recovery MRI is believed to be caused by gadolinium-based contrast agents crossing a disrupted blood-brain barrier. However, this hypothesis has never been directly verified in humans. METHODS: In this study, we analyzed cerebrospinal fluid samples of patients with HARM on imaging regarding the presence and concentration of gadolinium-based contrast agents. RESULTS: Gadobutrol was found in concentrations of approximately 50 µmol/L. Using phantom MRI experiments, we demonstrate that the detected concentrations are consistent with the observed HARM imaging pattern. CONCLUSIONS: Our study yields first direct evidence in humans that the imaging phenomenon HARM is indeed caused by leakage of gadolinium-based contrast agents into the cerebrospinal fluid.

Thrombolytic toxicity: blood brain barrier disruption in human ischemic stroke.

BACKGROUND: In experimental models of cerebral ischemia, thrombolytic drugs have been demonstrated to have a number of neurovascular toxic effects including blood brain barrier disruption. Early barrier opening caused by focal cerebral ischemia in human stroke can be assessed by the presence of gadolinium enhancement of cerebrospinal fluid, termed 'Hyperintense Acute Injury Marker' (HARM). METHODS: In a retrospective analysis, the frequency of HARM was studied in 140 patients, 38 receiving intra-arterial thrombolytics, 18 undergoing mechanical embolectomy, 24 receiving intravenous tissue plasminogen activator and 60 patients receiving no acute intervention. RESULTS: HARM was found in 66% of patients undergoing intra-arterial thrombolysis and 50% of patients receiving intravenous tissue plasminogen activator, compared to 28% of patients undergoing mechanical embolectomy and 30% of patients receiving no acute therapy (p = 0.002). Both thrombolytic therapy (p = 0.001) and age (p = 0.001) were independent predictors of HARM. HARM was an independent predictor of hemorrhagic transformation (p = 0.007). CONCLUSIONS: This is the first study in humans providing supportive evidence of the neurovascular toxic effects of thrombolytics and suggests that HARM may be used as a biomarker of blood brain barrier disruption in future research of acute stroke therapies.

High signal in the cerebrospinal fluid following prior gadolinium administration in a patient with renal impairment.

Increased signal intensity in the cerebrospinal fluid (CSF) on magnetic resonance imaging due to the presence of gadolinium is rarely observed, but has been seen in patients with brain or spinal pathology or underlying renal impairment. We report this phenomenon in a 66-year-old woman with diabetic nephropathy and discuss the possible pathogenesis of the scan findings. Recognition of this unusual finding, and features distinguishing it from other causes of high CSF signal intensity, such as subarachnoid haemorrhage and protein in the CSF, are emphasised to help prevent diagnostic errors.