An integrated mechanism of pediatric pseudotumor cerebri syndrome: evidence of bioenergetic and hormonal regulation of cerebrospinal fluid dynamics

Abstract

Pseudotumor cerebri syndrome (PTCS) is defined by the presence of elevated intracranial pressure (ICP) in the setting of normal brain parenchyma and cerebrospinal fluid (CSF). Headache, vision changes, and papilledema are common presenting features. Up to 10% of appropriately treated patients may experience permanent visual loss. The mechanism(s) underlying PTCS is unknown. PTCS occurs in association with a variety of conditions, including kidney disease, obesity, and adrenal insufficiency, suggesting endocrine and/or metabolic derangements may occur. Recent studies suggest that fluid and electrolyte balance in renal epithelia is regulated by a complex interaction of metabolic and hormonal factors; these cells share many of the same features as the choroid plexus cells in the central nervous system (CNS) responsible for regulation of CSF dynamics. Thus, we posit that similar factors may influence CSF dynamics in both types of fluid-sensitive tissues. Specifically, we hypothesize that, in patients with PTCS, mitochondrial metabolites (glutamate, succinate) and steroid hormones (cortisol, aldosterone) regulate CSF production and/or absorption. In this integrated mechanism review, we consider the clinical and molecular evidence for each metabolite and hormone in turn. We illustrate how related intracellular signaling cascades may converge in the choroid plexus, drawing on evidence from functionally similar tissues.

Presumed Pseudotumor Cerebri Syndrome After Withdrawal of Inhaled Glucocorticoids

“…5 This result suggests that it may be chronicity and adaptation to previous glucocorticoid exposure, rather than absolute reductions in cortisol levels per se, that predispose to the development of PTCS. 3 It has been hypothesized that cortisol may act at the mineralocorticoid response element to influence cerebrospinal fluid production via downstream effects on epithelial sodium channel and Na + /K + ATPase activity in the choroid plexus. 3 In addition, a potential role for tissue-specific "local" cortisol availability has been postulated.…”

“…3 It has been hypothesized that cortisol may act at the mineralocorticoid response element to influence cerebrospinal fluid production via downstream effects on epithelial sodium channel and Na + /K + ATPase activity in the choroid plexus. 3 In addition, a potential role for tissue-specific "local" cortisol availability has been postulated. Specifically, 11-β-hydroxysteroid dehydrogenase type 1 (HSD1) and type 2 (HSD2) regulate the local tissue availability of cortisol.…”

“…2 Although the unifying mechanism(s) underlying PTCS are incompletely understood, past clinical observations have suggested abnormal glucocorticoid metabolism may contribute to the pathophysiology of PTCS. 3 For example, PTCS has been described in patients with Addison disease, 4 after surgical resection of the pituitary tumors for Cushing disease, 5 and in adults after withdrawing of chronic systemic glucocorticoid therapy. 6 PTCS after withdrawal of systemic corticosteroids also has been described in children.…”

The role of puberty and adolescence in the pathobiology of pediatric multiple sclerosis

“…Adipose tissue contains aromatase, which may be a link between obesity and PTCS. Aromatase, which catalyses the production of oestrogens from plasma androstenedione, is more prevalent in the fat of the buttock regions (reflecting the typical female fat distribution) vs. the abdominal (visceral) regions [34][35][36]. Of note, the reports of the onset of PTCS in postmenopausal women following the initiation of hormone replacement therapy further support the notion of an oestrogen involvement in the pathophysiology of this condition [31-33, 37, 38].…”

“…Paediatric PTCS is known to occur in association with a broad variety of conditions, especially obesity and endocrine derangements (e.g., cortisol deficiency or excess, hyperandrogenism, hyperaldosteronism) [32,36]. Although pre-pubertal PTCS can occur in both genders and ages, post-pubertal PTCS is usually recorded in women during their reproductive age [34,35]: in this respect, it has been previously proposed that the proneness of some women to develop PTCS could be linked to an estrogenic gynecoid (pear-shaped) fat distribution [34].…”