Glucocorticoids May Decrease White Matter Integrity & Change Gray Matter Volume

I learned many lessons as a rheumatology fellow. Perhaps the most important lesson came from Michelle Petri, MD, MPH, lupus expert extraordinaire. “The p in prednisone stands for poison,” she said.

Although steroids play a significant role in the treatment of many rheumatologic diseases, her point is well-taken. Given The Rheumatologist’s readership, I see no need to review the list of known short- and long-term side effects of glucocorticoids. It’s long. A study in BMJ Open just made the list longer.¹

In August 2022, Merel van der Meulen, BSc, MD, PhD candidate, Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands, and colleagues share data demonstrating that the use of both systemic and inhaled glucocorticoids is associated with changes in several brain imaging parameters.¹

Background

Glucocorticoids are associated with a variety of neuropsychiatric symptoms and disorders, including—but not limited to—depression, mania and delirium.² What’s more, several studies have demonstrated the anatomical effects of glucocorticoids on the brain. Example: Cushing disease (i.e., chronic endogenous glucocorticoid excess secondary to a pituitary tumor) is associated with global cerebral atrophy, as well as decreased cortical thickness and gray matter volume in specific areas of the brain.^3,4

Studies investigating glucocorticoid overexposure and brain structure are small, and none have included subjects taking inhaled glucocorticoids. Van der Meulen et al. used data from the U.K. Biobank—a population-based prospective cohort containing in-depth genetic and health information from over half a million U.K. participants aged 40–69 at the time of recruitment. The researchers investigated whether differences in brain volumes and white matter microstructure could be detected between users and non-users of systemic or inhaled glucocorticoids.^1,5

The primary outcome of the study was the difference in imaging parameters between glucocorticoid users and non-users for brain regions of interest previously shown to be affected by long-term glucocorticoid exposure. Secondary outcomes included differences in cognitive and emotional functioning between glucocorticoid users and non-users.

‘This study may raise awareness for the potential psychiatric side effects associated with glucocorticoid use.’ —Dr. Van der Meulen

Summary of Research

Van der Meulen et al. examined patients taking systemic (n=222) or inhaled (n=557) glucocorticoids at the time of both T1-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). DTI characterizes microstructural changes and differences due to neuropathology and treatment.⁶ The study subjects also completed a series of cognitive tests and mental health questionnaires that assessed symptoms experienced over the preceding two weeks while taking glucocorticoids.

Subjects with a history of neurologic conditions or psychiatric disease, and those taking psychotropic medication were excluded from the study. Of note, “those with the psychiatric conditions most commonly associated with glucocorticoid use (i.e., anxiety, depression, mania and delirium) were studied so as not to exclude patients based on potentially glucocorticoid-related outcomes.”¹

Patients in the control group (n=24,106) included those who met the above criteria but hadn’t used glucocorticoids at any time point prior to or during imaging. These patients also didn’t have an endocrine disorder. The groups didn’t differ significantly with respect to sex, education or smoking status. However, the systemic glucocorticoid group was slightly older than the inhaled glucocorticoid group, and the inhaled glucocorticoid group had a higher body mass index and body fat percentage than the systemic glucocorticoid group. 

Both systemic and inhaled glucocorticoid use were associated with reduced white mater integrity compared with controls, with larger effect sizes in systemic glucocorticoid users. “If white matter integrity is reduced, this indicates that connections between brain regions essential for integrating information may be impaired,” says Dr. Van der Meulen.

Systemic glucocorticoid use was also associated with larger caudate gray matter volume. Inhaled glucocorticoid users had smaller amygdalas than controls. 

For secondary outcomes, systemic glucocorticoid users performed worse on the symbol digit substitution task, which assesses complex processing speed. They also reported more depressive symptoms, disinterest, tenseness/restlessness and tiredness/lethargy compared with controls.  Inhaled glucocorticoid users only reported more tiredness/lethargy. Of note, the authors write that “the observed mood-related effects may not be caused by glucocorticoid use per se but could also be related to the condition for which glucocorticoids were prescribed.”

Limitations: The cross-sectional nature of this study doesn’t permit formal conclusions on causality. Data regarding the dose and duration of glucocorticoid use aren’t available in the U.K. Biobank. Thus, thorough analyses on dose- or duration-dependent effects weren’t possible.

Implications for Clinical Practice

Dr. Van der Meulen was kind enough to share her take on the clinical implications of this fascinating research.

The Rheumatologist (TR): What do you think is the most interesting part of your research?

Dr. Van der Meulen: The finding that struck our research team most was the widespread reduction in white matter integrity that we found consistently in the brain regions that we studied. Historically, much research has focused on the effects of glucocorticoids on neurons, but this study adds to a growing body of evidence showing that an important part of glucocorticoid effects on the brain may be mediated by the glial cells in the white matter.

TR: What should physicians and other health care team members in practice take away from your research? How may it affect patient care or clinical practice?

Dr. Van der Meulen: In general, doctors are aware that glucocorticoids have side effects and are, therefore, careful to prescribe them only to the patients who really need them at the lowest possible dose. This study may raise awareness for the potential psychiatric side effects associated with glucocorticoid use.

TR: Was there anything about your findings that caught you by surprise?

Dr. Van der Meulen: We were surprised by the consistency of the white matter effects and by our finding that we could not only see these effects in systemic glucocorticoid users, but also to a limited extent in inhaled glucocorticoid users.

TR: What are directions for further research?

Dr. Van der Meulen: There are many questions that remain unanswered that we hope to address in the future. For example, how clinically relevant are these effects, and are they reversible? How do they depend on dose and duration of glucocorticoid use and the type of glucocorticoid medication used? And could selective glucocorticoid receptor modulators, a type of glucocorticoid-like medication that has a more selective effect—and therefore potentially has less side effects—prevent these effects from happening?

Conclusion

In summary, Dr. Van der Meulen and colleagues share fascinating new data that both systemic and inhaled glucocorticoids are associated with several brain imaging paraments, and this may contribute to the neuropsychiatric side effects of glucocorticoids. Unfortunately, the p in prednisone still stands for poison. As rheumatologists, we must remain vigilant about limiting glucocorticoid usage when able.

---

Samantha C. Shapiro, MD, is the executive editor of Harrison’s Principles of Internal Medicine. As a clinician educator, she practices telerheumatology and writes for both medical and lay audiences.

References

1. van der Meulen M, Amaya JM, Dekkers OM, et al. Association between use of systemic and inhaled glucocorticoids and changes in brain volume and white matter microstructure: a cross-sectional study using data from the U.K. Biobank. BMJ Open. 2022 Aug 30;12(8):e062446.
2. Judd LL, Schettler PJ, Brown ES, et al. Adverse consequences of glucocorticoid medication: Psychological, cognitive, and behavioral effects. Am J Psychiatry. 2014 Oct;171(10):1045–1051.
3. Bourdeau I, Bard C, Noël B, et al. Loss of brain volume in endogenous Cushing’s syndrome and its reversibility after correction of hypercortisolism. J Clin Endocrinol Metab. 2002 May;87(5):1949–1954.
4. Chen Y, Zhang J, Tan H, et al. Detrimental effects of hypercortisolism on brain structure and related risk factors. Sci Rep. 2020 Jul 29;10(1):12708.
5. U.K. Biobank: https://www.ukbiobank.ac.uk/.
6. Alexander AL, Lee JE, Lazar M, et al. Diffusion tensor imaging of the brain. Neurotherapeutics. 2007 Jul;4(3):316–329.