Previous glucocorticoid treatment in childhood and adolescence is associated with long-term differences in subcortical grey matter volume and microstructure

Abstract

Background Glucocorticoids are widely used in the treatment of several pediatric diseases with undisputed disease-related benefits. Perinatal exposure to high levels of glucocorticoids can have long-term adverse cerebral effects. In adults, glucocorticoid treatment has been associated with smaller volumes of subcortical grey matter structures. Recently, we observed smaller total brain volumes in children and adolescents treated with glucocorticoid during childhood compared to healthy controls. The possible long-term effects of glucocorticoid treatment during childhood on subcortical brain volume and microstructure remain unknown. Method We examined 30 children and adolescents, who had previously been treated with glucocorticoids for nephrotic syndrome or rheumatic disease, and 30 healthy volunteers. Patients and healthy control groups were matched by age, gender, and level of parent education. Participants underwent 3 T magnetic resonance (MR) brain imaging. T1-weighted and diffusion-weighted images were acquired. Volume and mean diffusivity (MD) measures were extracted for hippocampus, amygdala, nucleus accumbens, caudate nucleus and putamen. Multiple linear regression analyses were used to assess differences between patients and controls, and to evaluate possible dose-response relationships. A priori, we expected patients to display lower hippocampal and amygdala volumes. Results While children previously treated with glucocorticoids displayed smaller right hippocampal volumes than controls, this difference did not survive correction for multiple comparisons. Furthermore, patients as compared to controls showed lower right hippocampal MD, which remained when correcting for global changes in MD. The longer the time between the glucocorticoid treatment termination and MR-scan, the more right hippocampal MD values resembled that of healthy controls. Patient and controls did not differ in amygdala volume or MD. Analyses of the nucleus accumbens, caudate nucleus and putamen only revealed smaller putamen volumes in patients compared to controls, which remained significant when controlling for total brain volume. Conclusion The results suggest that extra-cerebral diseases during childhood treated with glucocorticoids may be associated with reduced subcortical grey matter volumes and lower right hippocampal mean diffusivity later in life. Our findings warrant replication and elaboration in larger, preferably prospective and longitudinal studies. Such studies may also allow disentangling disease-specific effects from possible glucocorticoid treatment effects.

Neurodevelopment in Term Infants with Normal Birthweight following Postnatal Systemic Steroid Exposure

“…A systemic review concluded that postnatal dexamethasone use in preterm infants is associated with reduced overall brain and cerebellar volumes [ 17 ]. In addition, perinatal exposure to glucocorticoids has been linked to structural brain changes and neurological and behavioral problems later in life, including cortical thinning, cerebral palsy, abnormal neurological examinations, and affective problems [ 18 , 19 ]. A meta-analysis concluded that the benefits of early postnatal dexamethasone treatment may not outweigh its adverse effects [ 20 ].…”

Comparison of two corticosteroid regimens on brain volumetrics in patients with Duchenne muscular dystrophy

“…29,30,47,48 While most of this research has been conducted in adults, a few studies have investigated the impact of corticosteroid treatment on the developing brain in children and found reduced cortical GMV in children treated with daily corticosteroids for epilepsy, rheumatic or nephrotic diseases. [25][26][27][28] However, it is important to note that the treatment duration for these conditions typically ranges from weeks to months, whereas individuals with DMD receive corticosteroid treatment starting from an early age (4-5 years) continuing into adulthood, resulting in a much longer treatment duration. In addition to GMV loss, recent research has suggested that corticosteroid exposure may impact WM tissue as it affects the proliferation of oligodendrocytes and the structure of myelin.…”

“…However, numerous studies in other populations have demonstrated an association between exposure to high corticosteroid levels, either endogenous due to Cushing's disease or exogenous due to systemic corticosteroid treatment, and global cerebral atrophy, cortical thinning, and volumetric changes in specific brain regions 29,30,47,48 . While most of this research has been conducted in adults, a few studies have investigated the impact of corticosteroid treatment on the developing brain in children and found reduced cortical GMV in children treated with daily corticosteroids for epilepsy, rheumatic or nephrotic diseases 25–28 . However, it is important to note that the treatment duration for these conditions typically ranges from weeks to months, whereas individuals with DMD receive corticosteroid treatment starting from an early age (4–5 years) continuing into adulthood, resulting in a much longer treatment duration.…”

“…[21][22][23][24] While studies investigating the cerebral effects of corticosteroid treatment in childhood are scarce, there is evidence that some corticosteroids induce brain atrophy in children and adolescents. [25][26][27][28] Studies in adults have linked subcortical and cortical atrophy to corticosteroid treatment, as well as decreased WM integrity. [29][30][31][32][33] Additionally, unfavorable behavioral changes and onset of psychiatric symptoms due to corticosteroid treatment have been described, also in the DMD population.…”

“…Corticosteroids can cross the blood–brain barrier and bind to mineralocorticoid and glucocorticoid receptors to affect gene transcription in all major cell types in the brain 21–24 . While studies investigating the cerebral effects of corticosteroid treatment in childhood are scarce, there is evidence that some corticosteroids induce brain atrophy in children and adolescents 25–28 . Studies in adults have linked subcortical and cortical atrophy to corticosteroid treatment, as well as decreased WM integrity 29–33 .…”