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Table 1.  
Selected Baseline Characteristics for Patients With vs Without Gadolinium Exposurea
Selected Baseline Characteristics for Patients With vs Without Gadolinium Exposurea
Table 2.  
New Diagnoses of Parkinsonism After MRIs (Not of the Brain or Spine) With or Without Gadolinium Exposure
New Diagnoses of Parkinsonism After MRIs (Not of the Brain or Spine) With or Without Gadolinium Exposure
1.
Ramalho  J, Semelka  RC, Ramalho  M, Nunes  RH, AlObaidy  M, Castillo  M.  Gadolinium-based contrast agent accumulation and toxicity [published online December 10, 2015].  AJNR Am J Neuroradiol. doi:10.3174/ajnr.A4615. PubMedGoogle Scholar
2.
Errante  Y, Cirimele  V, Mallio  CA, Di Lazzaro  V, Zobel  BB, Quattrocchi  CC.  Progressive increase of T1 signal intensity of the dentate nucleus on unenhanced magnetic resonance images is associated with cumulative doses of intravenously administered gadodiamide in patients with normal renal function, suggesting dechelation.  Invest Radiol. 2014;49(10):685-690.PubMedGoogle ScholarCrossref
3.
Münchau  A, Mathen  D, Cox  T, Quinn  NP, Marsden  CD, Bhatia  KP.  Unilateral lesions of the globus pallidus.  J Neurol Neurosurg Psychiatry. 2000;69(4):494-498.PubMedGoogle ScholarCrossref
4.
Butt  DA, Tu  K, Young  J,  et al.  A validation study of administrative data algorithms to identify patients with parkinsonism with prevalence and incidence trends.  Neuroepidemiology. 2014;43(1):28-37.PubMedGoogle ScholarCrossref
5.
Welk  B, McArthur  E, Fraser  L-A,  et al.  The risk of fall and fracture with the initiation of a prostate-selective α antagonist.  BMJ. 2015;351:h5398.PubMedGoogle ScholarCrossref
6.
Andersen  PK, Gill  RD.  Cox’s regression model for counting processes.  Ann Stat. 1982;10(4):1100-1120. doi:10.1214/aos/1176345976.Google ScholarCrossref
Research Letter
July 5, 2016

Association Between Gadolinium Contrast Exposure and the Risk of Parkinsonism

Author Affiliations
  • 1Department of Surgery, Western University, London, Canada
  • 2Institute for Clinical Evaluative Sciences, Ontario, Canada
  • 3Department of Clinical Neurological Sciences, Western University, London, Canada
  • 4Department of Medical Imaging, Western University, London, Canada
JAMA. 2016;316(1):96-98. doi:10.1001/jama.2016.8096

Gadolinium-based contrast agents are used for enhancement during magnetic resonance imaging (MRI). Safety concerns have emerged over retained gadolinium in the globus pallidi.1,2 Neurotoxic effects have been seen in animals and when gadolinium is given intrathecally in humans.1 In July 2015, the US Food and Drug Administration stated that it was unknown whether gadolinium deposits were harmful. The substantia nigra (affected in Parkinson disease) directs voluntary movement via signals to the globus pallidi. Consequences of damage to the globus pallidi may include parkinsonian symptoms.3 We conducted a population-based study to assess the association between gadolinium exposure and parkinsonism.

Methods

Sunnybrook Hospital granted ethics approval and deemed the study exempt from participant consent. Multiple linked administrative databases from Ontario, Canada, were used. The population has universal health care, and medication coverage is provided for those older than 65 years. Using fee codes submitted by radiologists, all patients older than 66 years who underwent an initial MRI between April 2003 and March 2013 were identified. Patients whose initial MRI was of the brain or spinal cord and those with prior parkinsonism or neurosurgery were excluded. Patients who were exposed to gadolinium-enhanced MRIs (modeled as a time-varying, cumulative count variable) were compared with patients who received non–gadolinium-enhanced MRIs. The primary outcome, assessed from the initial MRI until death, emigration, or March 2015, was a new diagnosis of parkinsonism based on a validated definition (sensitivity, 81.7%; specificity, 99.7%; positive predictive value, 78.0%; negative predictive value, 99.8%; accuracy, 99.5%; and disease prevalence, 1.4%) using diagnosis codes from hospital admissions and physician visits or a dispensed Parkinson disease–specific medication.4 We measured 105 covariates5 and evaluated significant inequalities between patients who underwent only non–gadolinium-enhanced MRIs and those who underwent 1 or more gadolinium-enhanced MRI. A subset of 38 covariates particularly relevant to parkinsonism (based on potential associations from the literature) or significantly different at baseline (standardized difference >10%) were included in a multivariable time-dependent extended Cox regression model using SAS (SAS Institute), version 9.4; the hazard ratio (HR) is interpreted as the hazard of parkinsonism per additional gadolinium exposure.6 Sensitivity analyses adjusting for covariates with standardized differences of 9% or 10% and defining parkinsonism without medications4 were performed. A 2-sided P value less than .05 was considered significant.

Results

Of the 246 557 patients (median age, 73 years [interquartile range, 69-78]; women, 54.9%) undergoing at least 1 MRI (not of the brain or spine) during the study period, 99 739 (40.5%) received at least 1 dose of gadolinium. The most common initial non–gadolinium-enhanced MRI was of an extremity (76.0%); the most common gadolinium-enhanced MRI was of the abdomen (39.2%). Among patients who underwent gadolinium-enhanced MRIs, 81.5% underwent a single study, and 2.5% underwent 4 or more gadolinium-enhanced studies. Incident parkinsonism developed in 1.16% of unexposed patients and 1.17% of those exposed to gadolinium. Selected covariates are summarized in Table 1 (and listed in eTable 1 in the Supplement). In adjusted analysis there was no significantly increased hazard of parkinsonism among patients with cumulative gadolinium exposure compared with those exposed to non–gadolinium-enhanced MRIs (HR, 1.04 [95% CI, 0.98-1.09], P = .18, Table 2). No significantly increased HR was found in either sensitivity analysis.

Discussion

In this population-based study, no significant association between gadolinium exposure and parkinsonism was found. This result does not support the hypothesis that gadolinium deposits in the globus pallidi lead to neuronal damage manifesting as parkinsonism. However, reports of other nonspecific symptoms (pain, cognitive changes) after gadolinium exposure require further study.1

Strengths of the study include a large cohort with a similar propensity to use MRIs, assessment of more than 100 baseline characteristics, and methodology accounting for the cumulative nature of gadolinium exposure. A study limitation is the potential for differential misclassification of the outcome. Given the components of the outcome definition, it seems likely to be more sensitive and less specific among those with gadolinium exposure, which would mean the actual HR may be lower than 1.04. Other limitations include the small number of patients who received 4 or more doses of gadolinium, the lack of generalizability to younger patients, the possibility of residual confounding from temporal trends in gadolinium usage not captured in the adjustment for year of initial MRI, and the inability to determine the specific type of gadolinium used.

Section Editor: Jody W. Zylke, MD, Deputy Editor.
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Article Information

Corresponding Author: Blayne Welk, MD, MSc, Department of Surgery and Epidemiology and Biostatistics, Division of Urology and Epidemiology and Biostatistics, Western University, Room B4-667, St Joseph's Health Care, 268 Grosvenor Street, London, ON N6A 4V2, Canada (bkwelk@gmail.com).

Author Contributions: Dr Welk and Mr McArthur had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

Acquisition, analysis, or interpretation of data: Welk, McArthur, Morrow, MacDonald.

Drafting of the manuscript: Welk.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: McArthur.

Administrative, technical, or material support: Morrow, MacDonald, Hayward.

Study supervision: Welk, Lum.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This project was conducted at the Institute for Clinical Evaluative Sciences (ICES) Western Site. ICES is funded by an annual grant from the Ontario Ministry of Health and Long-term Care. ICES Western is funded by an operating grant from the Academic Medical Organization of Southwestern Ontario.

Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The opinions, results, and conclusions are those of the authors, and no endorsement by the ICES, Ontario Ministry of Health and Long-term Care, or Academic Medical Organization of Southwestern Ontario is intended or should be inferred. Parts of this material are based on data and information compiled and provided by the Canadian Institute for Health Information (CIHI). However, the analyses, conclusions, opinions, and statements expressed herein are those of the author, and not necessarily those of CIHI.

Additional Contributions: We thank Stephanie Dixon, PhD (Institute for Clinical Evaluative Sciences), for her contributions to the study design and manuscript revisions. She was compensated for her assistance.

References
1.
Ramalho  J, Semelka  RC, Ramalho  M, Nunes  RH, AlObaidy  M, Castillo  M.  Gadolinium-based contrast agent accumulation and toxicity [published online December 10, 2015].  AJNR Am J Neuroradiol. doi:10.3174/ajnr.A4615. PubMedGoogle Scholar
2.
Errante  Y, Cirimele  V, Mallio  CA, Di Lazzaro  V, Zobel  BB, Quattrocchi  CC.  Progressive increase of T1 signal intensity of the dentate nucleus on unenhanced magnetic resonance images is associated with cumulative doses of intravenously administered gadodiamide in patients with normal renal function, suggesting dechelation.  Invest Radiol. 2014;49(10):685-690.PubMedGoogle ScholarCrossref
3.
Münchau  A, Mathen  D, Cox  T, Quinn  NP, Marsden  CD, Bhatia  KP.  Unilateral lesions of the globus pallidus.  J Neurol Neurosurg Psychiatry. 2000;69(4):494-498.PubMedGoogle ScholarCrossref
4.
Butt  DA, Tu  K, Young  J,  et al.  A validation study of administrative data algorithms to identify patients with parkinsonism with prevalence and incidence trends.  Neuroepidemiology. 2014;43(1):28-37.PubMedGoogle ScholarCrossref
5.
Welk  B, McArthur  E, Fraser  L-A,  et al.  The risk of fall and fracture with the initiation of a prostate-selective α antagonist.  BMJ. 2015;351:h5398.PubMedGoogle ScholarCrossref
6.
Andersen  PK, Gill  RD.  Cox’s regression model for counting processes.  Ann Stat. 1982;10(4):1100-1120. doi:10.1214/aos/1176345976.Google ScholarCrossref
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