Adrenal Disorders and the Paediatric Brain: Pathophysiological Considerations and Clinical Implications

Abstract

Various neurological and psychiatric manifestations have been recorded in children with adrenal disorders. Based on literature review and on personal case-studies and case-series we focused on the pathophysiological and clinical implications of glucocorticoid-related, mineralcorticoid-related, and catecholamine-related paediatric nervous system involvement. Childhood Cushing syndrome can be associated with long-lasting cognitive deficits and abnormal behaviour, even after resolution of the hypercortisolism. Exposure to excessive replacement of exogenous glucocorticoids in the paediatric age group (e.g., during treatments for adrenal insufficiency) has been reported with neurological and magnetic resonance imaging (MRI) abnormalities (e.g., delayed myelination and brain atrophy) due to potential corticosteroid-related myelin damage in the developing brain and the possible impairment of limbic system ontogenesis. Idiopathic intracranial hypertension (IIH), a disorder of unclear pathophysiology characterised by increased cerebrospinal fluid (CSF) pressure, has been described in children with hypercortisolism, adrenal insufficiency, and hyperaldosteronism, reflecting the potential underlying involvement of the adrenal-brain axis in the regulation of CSF pressure homeostasis. Arterial hypertension caused by paediatric adenomas or tumours of the adrenal cortex or medulla has been associated with various hypertension-related neurological manifestations. The development and maturation of the central nervous system (CNS) through childhood is tightly regulated by intrinsic, paracrine, endocrine, and external modulators, and perturbations in any of these factors, including those related to adrenal hormone imbalance, could result in consequences that affect the structure and function of the paediatric brain. Animal experiments and clinical studies demonstrated that the developing (i.e., paediatric) CNS seems to be particularly vulnerable to alterations induced by adrenal disorders and/or supraphysiological doses of corticosteroids. Physicians should be aware of potential neurological manifestations in children with adrenal dysfunction to achieve better prevention and timely diagnosis and treatment of these disorders. Further studies are needed to explore the potential neurological, cognitive, and psychiatric long-term consequences of high doses of prolonged corticosteroid administration in childhood.

Long-term outcomes of children treated for Cushing’s disease: a single center experience

“…The more severe psychiatric and behavioral symptoms at diagnosis improved significantly after cure. Hypercortisolemia may induce atrophic changes in the CNS, with volume loss in the temporal lobe, amygdala and the hippocampus [38, 39]. These effects might contribute to the behavioral and cognitive changes seen in adult and pediatric CS patients [39].…”

“…Hypercortisolemia may induce atrophic changes in the CNS, with volume loss in the temporal lobe, amygdala and the hippocampus [38, 39]. These effects might contribute to the behavioral and cognitive changes seen in adult and pediatric CS patients [39]. One small pediatric study reports declining cognitive function 1 year after cure of CS even after regaining lost brain volume [36].…”

Unpredictable Chronic Stress Alters Adenosine Metabolism in Zebrafish Brain

“…Glutamate is the most abundant excitatory neurotransmitter and may be potently toxic since the excessive release of glutamate could induce cell death via excitotoxicity [72,73]. Furthermore, it is described that glucocorticoids may increase the accumulation of glutamate, stimulate the N-methyl-D-aspartate (NDMA) receptors, and increase cytosolic intracellular Ca 2+ in postsynaptic neurons that activate various processes leading to neuronal death [74,75]. It has been shown that this excitotoxic effect is involved in a variety of neurological disorders [76][77][78].…”

Encephalocraniocutaneous Lipomatosis (Haberland Syndrome or Fishman Syndrome)

“…39,40 Neuroimaging studies are an important part of the diagnosis of neurocutaneous and neurologic disorders. [41][42][43][44][45][46][47] Intraspinal and intracranial lipomas are typical findings of ECCL (►Figs. 2 and 3).…”