Keiko Toyoda

Gadolinium-based Contrast Agent Accumulates in the Brain Even in Subjects without Severe Renal Dysfunction: Evaluation of Autopsy Brain Specimens with Inductively Coupled Plasma Mass Spectroscopy

PURPOSE To use inductively coupled plasma mass spectroscopy (ICP-MS) to evaluate gadolinium accumulation in brain tissues, including the dentate nucleus (DN) and globus pallidus (GP), in subjects who received a gadolinium-based contrast agent (GBCA). MATERIALS AND METHODS Institutional review board approval was obtained for this study. Written informed consent for postmortem investigation was obtained either from the subject prior to his or her death or afterward from the subjects relatives. Brain tissues obtained at autopsy in five subjects who received a linear GBCA (GBCA group) and five subjects with no history of GBCA administration (non-GBCA group) were examined with ICP-MS. Formalin-fixed DN tissue, the inner segment of the GP, cerebellar white matter, the frontal lobe cortex, and frontal lobe white matter were obtained, and their gadolinium concentrations were measured. None of the subjects had received a diagnosis of severely compromised renal function (estimated glomerular filtration rate <45 mL/min/1.73 m(2)) or acute renal failure. Fisher permutation test was used to compare gadolinium concentrations between the two groups and among brain regions. RESULTS Gadolinium was detected in all specimens in the GBCA agent group (mean, 0.25 µg per gram of brain tissue ± 0.44 [standard deviation]), with significantly higher concentrations in each region (P = .004 vs the non-GBCA group for all regions). In the GBCA group, the DN and GP showed significantly higher gadolinium concentrations (mean, 0.44 µg/g ± 0.63) than other regions (0.12 µg/g ± 0.16) (P = .029). CONCLUSION Even in subjects without severe renal dysfunction, GBCA administration causes gadolinium accumulation in the brain, especially in the DN and GP.

High Signal Intensity in Dentate Nucleus on Unenhanced T1-weighted MR Images: Association with Linear versus Macrocyclic Gadolinium Chelate Administration

PURPOSE To assess whether an association exists between hyperintensity in the dentate nucleus (DN) on unenhanced T1-weighted magnetic resonance (MR) images and previous administration of gadolinium-based contrast agents (GBCAs) that contain different types of gadolinium chelates. MATERIALS AND METHODS The institutional review board approved this study. Written informed consent was waived because this was a retrospective study. Evaluated were 127 cases among 360 consecutive patients who underwent contrast agent-enhanced brain MR imaging. Two radiologists conducted visual evaluation and quantitative analysis on unenhanced T1-weighted MR images by using regions of interest. DN-to-cerebellum (DN/cerebellum) signal intensity ratios were calculated and the relationship between DN/cerebellum and several factors was evaluated, including the number of previous linear chelate and/or macrocyclic GBCA administrations by using a generalized additive model. The Akaike information criterion was used in model selection. Interobserver correlation was evaluated with paired t tests and the Lin concordance correlation coefficient. RESULTS The images of nine patients (7.1%) showed hyperintensity in the DN. Twenty-three patients (18.1%) received linear GBCAs (median, two patients; maximum, 11 patients), 36 patients (28.3%) received macrocyclic GBCAs (median, two patients; maximum, 15 patients), 14 patients (11.0%) received both types of GBCA (linear [median, two patients; maximum, five patients] and macrocyclic [median, three patients; maximum, eight patients]), and 54 patients (42.5%) had no history of administration of gadolinium chelate. Interobserver correlation was almost perfect (0.992 [95% confidence interval: 0.990, 0.994]). The DN/cerebellum ratio was associated with linear GBCA (P < .001), but not with macrocyclic GBCA exposure (P = .875). According to the Akaike information criterion, only linear GBCA was selected for the final model, and the DN/cerebellum ratio had strong association only with linear GBCA. CONCLUSION Hyperintensity in the DN on unenhanced T1-weighted MR images is associated with previous administration of linear GBCA, while the previous administration of macrocyclic GBCAs showed no such association.

Brain gadolinium deposition after administration of gadolinium-based contrast agents

Gadolinium-based contrast agents (GBCAs) consist of gadolinium ions and a chelating agent that binds the gadolinium ion tightly so that its toxicity is not manifested. However, in 2013, an association between brain MRI abnormalities and a history of GBCA administration was first reported. Even in patients with normal renal function, increased signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted images showed a positive correlation with previous exposure to linear chelate type GBCAs, but not to macrocyclic chelate type ones. This difference of GBCAs is speculated to reflect the stability of GBCAs, and de-chelated gadolinium deposition has been strongly suspected. Using inductively coupled plasma mass spectroscopy, gadolinium was detected from patients’ brains with a history of repeated GBCA administration. In some cases, the gadolinium concentration of a patient’s brain with normal renal function exceeded the gadolinium concentration of the skin in nephrogenic systemic fibrosis patients, but without any histological change. The actual risk has not been documented yet, but it seems important to consider the potential unknown risks of residual gadolinium in our decisions regarding GBCA administration, and to make efforts to minimize any residual gadolinium in the patient’s body.

Gadolinium deposition in the brain

Gadolinium is highly toxic. Gadolinium-based contrast agents (GBCAs) consist of gadolinium ions and a chelating agent that binds the gadolinium ion tightly in order not to manifest its toxicity. Knowledge regarding gadolinium deposition in patients with normal renal function has advanced dramatically. Since 2014, increasing attention has been given to residual gadolinium known to accumulate in the tissues of patients with normal renal function. High signal intensity on T1-weighted images (T1WI) in the dentate nucleus, globus pallidus, and pulvinar region of the thalamus correlate roughly with the number of previous GBCA administrations. Pathological analyses have revealed that residual gadolinium is deposited not only in these brain regions, but also in extracranial tissues such as liver, skin and bone. The risks attendant with these deposits are unknown. Common sense dictates that gadolinium deposition be kept as low as possible, and that gadolinium contrast agents be used only when absolutely necessary, with preferential use of macrocyclic chelates, which seem to be deposited at lower concentrations.

Gadolinium Deposition after Contrast-enhanced MR Imaging

Editor: We wish to commend Dr McDonald and colleagues for their January 2015 Radiology article entitled “Intracranial Gadolinium Deposition after Contrastenhanced MR Imaging” (1). The authors evaluated the association between the previous administration of a gadolinium-based contrast agent (GBCA) and the signal intensity of the dentate nucleus, pulvinar of thalamus, and globus pallidus on unenhanced magnetic resonance (MR) images in normal renal function. They also proved the association between the exposure amount of GBCA and Disclosures of Conflicts of Interest: T.K. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: received a grant from Eisai. Other relationships: disclosed no relevant relationships. M.M. disclosed no relevant relationships. H.O. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: received a grant from Bayer Healthcare. Other relationships: disclosed no relevant relationships. K.T. disclosed no relevant relationships. S.F. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: received grants from Bayer Healthcare, Eisai, Daicchi Sankyo, and Terumo. Other relationships: disclosed no relevant relationships.

Distribution and chemical forms of gadolinium in the brain: a review

In the 3 years since residual gadolinium-based contrast agent (GBCA) in the brain was first reported, much has been learned about its accumulation, including the pathway of GBCA entry into the brain, the brain distribution of GBCA and its excretion. Here we review recent progress in understanding the routes of gadolinium deposition in brain structures.

Contribution of metals to brain MR signal intensity: review articles

Various metals are essential nutrients in humans, and metal shortages lead to a variety of deficiency diseases. Metal concentration abnormalities may cause metal deposition in the brain, and magnetic resonance imaging (MRI) is the most potent and sensitive technique now available for detecting metal deposition given the difficulties associated with performing brain tissue biopsy. However, the brain contains many kinds of metals that affect the signal intensity of MRI, which has led to numerous misunderstandings in the history of metal analysis. We reviewed the history of brain metal analysis with histologic findings. Typically, manganese overload causes high signal intensity on T1-weighted images (T1WI) in the globus pallidus, iron overload causes low signal intensity in the globus pallidus on T2-weighted images, and gadolinium deposition causes high signal intensity in the dentate nucleus, globus pallidus, and pulvinar of thalamus on T1WI. However, because nonparamagnetic materials and other coexisting metals also affect the signal intensity of brain MRI, the quantitative analysis of metal concentrations is difficult. Thus, when analyzing metal deposition using MRI, caution should be exercised when interpreting the validity and reliability of the obtained data.

Brain magnetic resonance findings in infective endocarditis with neurological complications

PurposeDiagnosing infective endocarditis and its complications can be difficult because of the nonspecific symptoms. We reviewed findings of intracranial abnormalities on magnetic resonance imaging (MRI) in 14 patients with neurological complications and herein discuss the overall intracranial MRI findings.Materials and methodsWe retrospectively reviewed patients with infective endocarditis from August 2004 to August 2006. Brain MRI, the causative bacteria, and abnormal neurological symptoms were reviewed for 14 patients with neurological complications.ResultsOf the 14 patients, 13 showed intracranial abnormalities on MRI. Embolization was seen in 10 patients, hemorrhage in 3, abscess formation in 3, and encephalitis in 2. Hyperintense lesions with a central hypointense area on T2-weighted and/or T2*-weighted imaging (Bull’s-eye-like lesion) were seen in four patients. A combination of these intracranial abnormalities was observed in 6 patients.ConclusionThe MRI findings associated with infective endocarditis are wide-ranging: embolization, hemorrhage, meningitis, cerebritis, abscess, the bull’s-eye-like lesion. Clinicians should consider the possibility of infective endocarditis in patients with unknown fever and neurological abnormality. Brain MRI should be promptly performed for those patients, and T2*-weighted imaging is recommended for an early diagnosis of infective endocarditis.

Primary Non-Hodgkin Lymphoma of the Skull Base Presenting with Garcin Syndrome: MRI Manifestations

Primary non‐Hodgkin lymphoma of the skull base is a rare disorder. We report a case of primary non‐Hodgkin lymphoma of the skull base presenting with Garcin syndrome. MRI revealed peculiar lesions in the cavernous sinus, clivus, and occipital bone. Diagnosis was made by biopsy of the tumor in the cavernous sinus.

Multicenter, multivendor phantom study to validate proton density fat fraction and T2* values calculated using vendor-provided 6-point DIXON methods

PURPOSE To evaluate the reproducibility of proton density fat fraction (PDFF) and T2* in a fat-water phantom on three different 3 T MRI systems using 6-point DIXON methods. METHODS A phantom which included varying fat volume percentages (true fat fraction [FF]) was scanned by three 3 T MR machines, and PDFF and T2* were measured. RESULTS The mean difference between true FF and PDFF was small in all vendors (-2.11% to 0.41%). However, the difference ratio for T2* values was large among vendors (1.79 to 3.36). CONCLUSIONS True FF and PDFF were consistent across vendors; however, T2* varied greatly.