Is Gadolinium Staining of the Brain a Real Concern When Ordering Brain MRI?: Pro vs Con

The convenience and availability of neuroimaging with MRI over the past few decades have led to increased utilization. Brain MRI is a powerful diagnostic tool frequently used in neurologic, ophthalmologic, and neuroophthalmic practices.

Point Counter-Point Section Editors: Andrew G. Lee, MD Gregory P. Van Stavern, MD Is Gadolinium Staining of the Brain a Real Concern When Ordering Brain MRI?: Pro vs Con Fiona E. Costello, MD, Julie M. Falardeau, MD, Andrew G. Lee, MD, Gregory P. Van Stavern, MD Introduction by Andrew G. Lee, MD, and Greg Van Stavern, MD The convenience and availability of neuroimaging with MRI over the past few decades have led to increased utilization. Brain MRI is a powerful diagnostic tool frequently used in neurologic, ophthalmologic, and neuroophthalmic practices. Gadolinium is a rare earth element with powerful paramagnetic properties that make it an ideal contrast agent for MRI and MR angiography. The addition of gadolinium increases the diagnostic yield of brain MRI for a wide variety of pathologic conditions including demyelinating disease, tumors, and vascular malformations. For certain conditions (particularly multiple sclerosis and brain tumors), patients may receive multiple MRI scans with gadolinium over time, and the recent discovery of “gadolinium staining” of the brain in some patients has raised concern about whether the routine use of gadolinium should be reconsidered. Two experts, Fiona Costello, MD, and Julie Falardeau, MD, debate this topic. “Is Gadolinium (Gd) Staining of the Brain a Real Concern When Ordering Brain MRI?” Yes modifying agents, and identify treatment complications Fiona Costello, MD Cranial MRI is the mainstay of imaging tools in neuroophthalmology and many other neurologic disciplines. Anterior visual pathway lesions, for example, are investigated with gadolinium enhanced T1 sequences of the brain and orbits to distinguish inflammatory, infectious, and tumor-based pathologies (1). For patients with a suspected or established diagnosis of multiple sclerosis (MS), there is currently no alternative imaging technique to postcontrast MRI that reveals equivalent biological information about subclinical inflammatory disease activity (2–4). Specifically, Gd enhancement on T1 spin-echo or gradient-echo images captures evidence of blood–brain barrier disruption and reflects pathophysiological features of inflammatory demyelination (2–4). Postcontrast T1 MRI scans are necessary to optimize diagnostic sensitivity and specificity, capture disease activity over time, determine effects of diseaseDepartments of Clinical Neurosciences and Surgery (FC), Cumming School of Medicine, University of Calgary, Calgary, Canada; Casey Eye Institute (JF), Oregon Health and Science University, Portland, Oregon; Blanton Eye Institute (AGL), Houston Methodist Hospital, Houston, Texas; and Department of Ophthalmology and Visual Sciences (GPVS), Washington University in St. Louis School of Medicine, St Louis, Missouri. The authors report no conflicts of interest. Address correspondence to Gregory P. Van Stavern, MD, Department of Ophthalmology and Visual Sciences, Washington University in St. Louis School of Medicine, St Louis, MO 63110; E-mail: [e-mail] Costello et al: J Neuro-Ophthalmol 2022; 42: 535-540 (2). In the setting of MS and many chronic neurologic conditions, Gd-enhanced MRI evaluation is for all intents and purposes the standard of care. The use of Gd-based contrast agents (GBCAs) is generally safe and effective. In fact, GBCAs have been approved for clinical use for over 30 years, with over 30 million doses administered worldwide per annum (3,5,6). Allergic and adverse reactions are infrequent but may be severe (6). In 2006, linear GBCA agents were first implicated in the development of nephrogenic systemic fibrosis (NSF) in patients with renal impairment (3–7). This potentially life-threatening syndrome is characterized by fibrosis of the skin, joints, and internal organs (4). Consequently, the administration of linear GBCAs was banned in patients with impaired renal function (4). This action proved highly effective: In a recent meta-analysis, the risk of NSF after Group II GBCA administration was only 0.07%, even in patients with late-stage chronic kidney disease (3,8). In 2014, Kanda et al (9) identified high signal intensities in the dentate nuclei and globus pallidi on unenhanced T1 MRI studies among 19 patients who had previously received at least 6 doses of linear GBCAs compared with 16 patients who underwent noncontrast MRI studies. Importantly, this retrospective study revealed a dose relationship between gadolinium staining and a history of GBCA administration, which was independent of renal function (5,9). The phenomenon, since coined 535 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point “Gadolinium Deposition Disease (GDD)” (10) (Fig. 1), has been observed among different patient populations (including individuals with MS and meningiomas) who have undergone longitudinal follow-up with repeat enhanced MRI scans (5,11). In related work, Nehra et al reported gadolinium accumulation within the cerebrospinal fluid of patients who received gadobutrol, a macrocytic GBCA (5,12). McDonald et al (13) described Gd deposition in human brain tissue of adults who received gadodiamide; in animal studies, these same investigators showed that gadolinium tissue deposition in rats was 2–4 times higher after the administration of linear GBCAs (gadodiamide and gadopentetate dimeglumine) compared with macrocyclic agents (gadobutrol and gadoteridol) (5,13). Gd deposition in the brain is believed to be a kinetic process that varies with GBCA subtype (14–16). Broadly speaking, linear GBCAs are considered less stable than their macrocyclic counterparts. Consequently, linear GBCAs have been associated with a greater chance of Gd staining, whereas brain accumulation of Gd from macrocyclic agents is believed to occur at very low levels (15,16). The pathogenic mechanisms that underpin Gd deposition are not well elucidated but may be linked to dechelation effects of free Gd released by unstable GBCAs, transmetallation, active metal transporters in cell membranes, and/or the glymphatic system (16). Currently, the impact of patientrelated factors on Gd deposition dynamics is similarly unclear and requires further study (15,16). Suffice to say, a certain threshold of exposure likely needs to be reached to cause hyperintense MRI signals after repeat injections of linear GBCAs (15). In a study of patients with meningiomas who were followed with serial imaging, 6 or more gadodiamide-enhanced MRI scans were required to reveal T1 hyperintensity signal changes in the dentate nuclei (6,15,16). Other investigators have reported that at least 4–6 injections of linear GBCAs are required to cause a visually detectable T1 signal findings (15,17–19). Autopsy studies on human subjects exposed to gadodiamide have demonstrated a dose-dependent relationship between injection doses and Gd deposition (20). The long-term implications of Gd staining in the brain are poorly understood. There are emerging reports suggesting that GDD may be associated with headache, confusion, and limb pain (10,21). In preclinical work, neuronal cell death has been linked to increased exposure of human neurons to GBCAs, prompting speculation that gadoliniumcontaining MRI contrast agents may have toxic effects on mitochondrial respiratory function and cell viability (22). The predilection for Gd deposition in basal ganglia structures has raised speculation regarding extrapyramidal system dysfunction and Parkinsonism in later life (16), but there is no robust clinical evidence to substantiate these fears. In fact, there are no data demonstrating deleterious effects of Gd deposition in the brain, human studies, or rat models. Unfortunately, the absence of evidence is not evidence of absence. Accordingly, the International Society for Magnetic FIG. 1. T1 hyperintensity in the globus pallidi, posterior thalami, and dentate nuclei (arrows), in a patient who has undergone numerous brain and abdominal MRIs for screening of tumors related to von Hippel–Lindau. Image courtesy of Manu Goyal, MD, Mallinckrodt Institute of Radiology, Washington University in St. Louis School of Medicine. 536 Costello et al: J Neuro-Ophthalmol 2022; 42: 535-540 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point Resonance in Medicine (ISMRM) (23) has urged caution regarding the use of GBCAs and suggested that these agents are administered with prudence. Health care professionals should consider the necessity of repetitive GBCA dosing in MRI treatment protocols and adhere to the as low as reasonably achievable (ALARA) principle, by using these agents only when essential for clinical management (4–6,14–16,22). Moreover, patient education and informed consent need to be emphasized in shared decision making regarding GBCA administration (5). Finally, clinicians should maintain careful institutional records of administered agents, review effects of gadolinium deposition in those receiving multiple doses, and report adverse events to the FDA’s MedWatch Safety Information and Adverse Event Reporting or equivalent regulatory agencies (23). Is Gadolinium (Gd) Staining of the Brain a Real Concern When Ordering Brain MRI?: CON Julie Falardeau, MD dobenate, gadodiamide, and gadoxetate) are particularly As noted above, GBCAs are widely used for diagnosing or monitoring disease progress on MRI, and each year, over 30 million doses of GBCAs are used worldwide, and more than 300 million doses have been administrated since their introduction (6). They are generally well tolerated and are considered safe with the exception of NSF, a potentially debilitating condition seen in patients with renal failure and GBCA exposure. Since 2014, the medical literature has seen several studies reported increased signal intensity involving the deep nuclei of the brain on unenhanced T1 MRI after repeated administration of GBCAs. Gd deposits have been confirmed in brain tissue through human autopsy studies and animal studies, and these deposits are primarily found in the dentate nucleus (DN) and globus pallidus (GP). Although both the linear and macrocyclic GBCAs have the potential to collect in the brain, linear agents (e.g., gadopentetate, ga- prone to deposition (24,25). In 2016, GDD was introduced as a new pathologic entity related to GBCAs. Semelka et al (26). first described a constellation of self-reported symptoms in patients with normal renal function who had received GBCAs and went on to propose the diagnostic criteria for GDD. To receive a diagnosis of GDD, a patient must demonstrate at least 3 of the following symptoms within a period of hours to 2 months post-GBCA administration: (1) peripheral neuropathic pain in either a glove and stocking or generalized distribution; (2) joint stiffness, muscle spasms, buzzing sensation, and fatigue; (3) headache; (4) clouded mentation; and (5) distal extremity and skin substrate thickening, discoloration, and pain. The description of this novel “disease” entity quickly attracted the attention of the medical community, regulatory agencies, and personal injury attorneys (27). From Deposition to Disease: Does “Gadolinium Deposition Disease” Truly Exist? Based on the scientific literature, GDD is still only a proposed disease process with no clear proof of its true existence (28). Following the first reports of GDD, the US Food and Drug Administration (FDA) convened in 2017 the Medical Imaging Drugs Advisory Committee and the panel concluded with “fair uniformity that there is no evidence of a causal relationship between the symptoms and signs in patients with normal renal function and the retention of gadolinium”(27,29). Although restricting the use of some linear GBCAs, the European Medicines Agency also concluded in 2017 that “there is currently no evidence that Gd deposition in the brain has caused any harm to patients” (30). Layne et al (31) reviewed clinical studies evaluating clinical signs or symptoms related to potential gadolinium toxicity post-GBCA exposure in subjects with normal renal function. The authors pointed out that most of these studies offered data from anonymous online surveys that recruited participants from support groups for people who self-identified as having GBCA-induced toxicity, with questions focusing on their reported symptoms and signs. Given Costello et al: J Neuro-Ophthalmol 2022; 42: 535-540 the significant selection bias and lack of clinical information to exclude alternative medical diagnoses, such studies should not be referenced as a justification or proof that GDD exits as a novel pathologic entity. Furthermore, despite the fact that gadolinium deposition primarily occurs within the DN and GP, none of the patients in all clinical studies complained of movement disorders. They reported generalized sensory symptoms, which are not expected to occur with lesions in these parts of the brain. To further explore the possibility of clinically significant damage to the GP, Welk et al (32) conducted a populationbased study to assess the association between Gd exposure and Parkinsonism, and in this large cohort of 99,739 patients receiving at least 1 dose of GBCA, no significant association between Gd exposure and Parkinsonism was found. Vymazal et al (33) assessed the neurological and neuropsychological status of 4 patients who received at least 50 injections of GBCA. The authors concluded that multiple applications of both the linear and macrocyclic GBCAs over a period of 13–15 years did not lead to clinical impairment related to Gd deposition in the deep brain nuclei. 537 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point Studies applying imaging techniques to evaluate brain microstructural and functional integrity, such as sodium MR imaging (34) and diffusion-weighted imaging (35), in multiple sclerosis patients receiving cumulative doses of GBCA showed preservation of tissue integrity of the DN despite visualized gadolinium deposition in this area. Similarly, a study looking at resting-state functional MR imaging connectivity in Crohn patients with high signal intensity on T1 images of the DN on unenhanced imaging did not show any DN functional changes (36). In 2019, Lyapustina et al (37) reviewed the current knowledge surrounding GBCAs and GDD and concluded that for the time being, there is no evidence to support a causal relationship between GBCA administration and the reported symptoms and NSF remains the only proven disease entity associated with GBCA exposure. The authors also emphasized that chelation therapy, as promoted by some clinicians, is not approved for this indication and carries unwarranted risk without documented efficacy. In a rat model, Ayers-Ringler et al (21) recently showed no clinical evidence of neurotoxicity after exposure to linear and macrocyclic GBCAs at supradiagnostic doses. In summary, although the clinical meaning of GBCA brain deposition remains under scrutiny, no direct relationship of causality with an impact on neurologic and neurocognitive functions has been reported to date. A disease entity that is strictly based on largely subjective patient-reported symptomatology should not cloud our decision making when investigating patients with neurologic or neuro-ophthalmic disorders. If a patient has a condition requiring evaluation with MRI, the risk/benefit ratio still strongly favors administration of Gd when indicated. Although patients or parents maintain autonomy to decline the use of GBCA, they should be informed that for the time being, (1) there is no documented permanent severe adverse effects related to gadolinium deposition in the brain, (2) GDD remains unproven scientifically, and (3) there is substantial convergent agreement on this subject among international organizations and regulatory agencies such as the FDA, European Medicines Agency, American College of Radiology, American Society of Neuroradiology, International Society for Magnetic Resonance in Medicine, and European Society for Magnetic Resonance in Medicine and Biology (38). Rebuttal—Dr. Costello Dr. Falardeau and I are in full agreement regarding many issues pertaining to Gd deposition both as a phenomenon and, indeed, relating to GDD as a proposed disease. Currently, there is no evidence that Gd staining in the brain poses any threat to humans. Yet, as my colleague has rightly pointed out, lack of evidence does not thwart the spread of misinformation nor does it prevent the financially motivated among us from seeking monetary gain. Thus, to protect patients and clinicians from the perils of mistruths, we need more information. Recent publications have shown Gd deposition to be a concentration-dependent process that affects adults and children, manifesting as high signal intensities in the globus pallidus and dentate nucleus on unenhanced T1 images. Residual gadolinium is deposited not only in the brain but also in extracranial tissues such as liver, skin, and bone. Yet, Gd-enhanced MRI studies are the standard of care in the diagnosis and surveillance of many central nervous system disorders. Moreover, for lifelong neurological diseases such as MS, developing systematic MRI protocols is the first step to building large databases; these, in turn, facilitate epidemiological studies and give rise to deep learning algorithms that ultimately benefit patients, doctors, and industry regulators (39). Accordingly, the determination of when and why to use Gd, along with other personalized care decisions, should be left to individual patients and their physicians. As clinicians, we are the “gatekeepers” who ultimately bear the responsibility of iatrogenic complications (5). For 538 this reason, neuro-ophthalmologists should remain knowledgeable regarding the evolving literature on Gd staining in the brain. Other practice steps to consider include: (1) maintaining records and clinical outcomes regarding use of Gd in patient care, (2) increasing patient education and incorporating informed consent and shared decision making when Gd administration occurs and when applicable, and (3) participating in institutional outcome reviews and follow-up for Gd deposition in those receiving multiple doses (5). Finally, the Gd staining debate may be seen as an opportunity for innovation, particularly because there are inherent limitations to relying on structural markers, including MRI, in the management of central nervous system diseases. Recent progress in the field of artificial intelligence, for example, has shown that deep learning programs may enhance existing methods used to detect, segment, and classify MS lesions (39). Furthermore, for individuals with established pituitary lesions, implementing structure–function models using standard automated perimetry and optical coherence tomography measures of retinal neuroaxonal integrity may help reduce the frequency of MRI studies and inform surgical decision making for carefully monitored patients. Certainly, MRI will remain a cornerstone of neuro-ophthalmic practice for the foreseeable future. With this in mind, it behoves us all to ensure that the protocols we use are safe, standardized, and optimized to provide the best possible care for our patients. Costello et al: J Neuro-Ophthalmol 2022; 42: 535-540 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point Rebuttal—Dr. Falardeau Dr. Costello mentions that there are emerging reports suggesting that Gd may be associated with headache, confusion, and limb pain. I would like to point out that with the exception of a small case series of 4 patients who did have a physical examination in addition to history taking, all other reports were strictly based on self-reported symptoms. The preclinical study reporting toxic effect of GBCA on mitochondrial respiratory function and cell viability deserves some attention. However, extrapolating the data to the human brain should be performed with caution. This study was conducted in cell culture, with a culture medium that is very different from the human brain. Contrast agents in culture medium have a much easier access to cell membranes, and cells in culture have a different environment to those in the brain. Gd deposition in human brain tissue unarguably exits, and I agree with Dr. Costello that clinicians should avoid ordering serial contrast-enhanced MRI studies when a noncontrast MRI can provide adequate information. However, given the lack of evidence of clinical harm because of GBCA deposition in the brain, the medical community needs to be mindful of the potential harm from overprotective measures against GBCA use in clinical practice. As reiterated by Dr. Costello, there are currently no published data from well-designed studies that support a link between brain Gd deposition and the development of clinical sequelae. Although the absence of evidence is not evidence of absence, the risk of GBCA use should be judged on the basis of facts rather than conjecture and speculations. Conclusion—Drs. Lee and Van Stavern The decision to order any diagnostic test including Gdenhanced cranial and spinal MRI requires balancing risks and benefits. The final decision may be heavily affected by the degree to which the results change patient care. The Gd staining discussed here is concerning, but as the authors mentioned, it remains unclear whether it is clinically significant. Conversely, not including Gd in certain cases may result in missed diagnosis or delay in diagnosis. It is likely based on the sheer numbers of Gdenhanced MR studies being performed annually that the risk from Gd deposition is relatively low (and may be on the same order as the risks of radiation from computerized tomography). The point may be moot because newer generation Gd agents have emerged on the market which seemed to have even lower risk of gadolinium staining. Thus, whether not to include Gd routinely should be decided on a case by case basis, guided in part by the differential diagnosis, and how the results might affect patient management. Patients however probably should be informed of the risks (albeit small) for GDD. Further research will likely be necessary to answer the question more definitively. REFERENCES 8. Woolen SA, Shankar PR, Gagnier JJ, MacEachern MP, Singer L, Davenport MS. 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