Title | Prevalence of Adrenal Insufficiency and Glucocorticoid Use in Pediatric Pseudotumor Cerebri Syndrome |
Creator | Alfonso Hoyos-Martinez, MD; Vincent E. Horne, MD; Alexis C. Wood, PhD; Veeral Shah, MD, PhD |
Affiliation | Department of Pediatrics, Section of Pediatric Diabetes and Endocrinology (AH-M, VEH), Baylor College of Medicine j Texas Children's Hospital, Houston, Texas; USDA/ARS Children's Nutrition Research Center (ACW), Houston, Texas; Department of Ophthalmology (VS), Baylor College of Medicine, Houston, Texas; Cincinnati Children's Hospital Medical Center (VS), Abrahamson Pediatric Eye Institute/Division of Pediatric Ophthalmology, Cincinnati, Ohio; and Department of Ophthalmology (VS), University of Cincinnati, Cincinnati, Ohio |
Abstract | The pathophysiology underlying pseudotumor cerebri syndrome (PTCS) is complex and not well under- stood. There are clear differences between PTCS in adults and pediatrics. Few and isolated case reports have suggested that adrenal function may be involved, yet no large cohort study has examined this relationship. |
Subject | PTCS; Pediatrics; Adrenals |
OCR Text | Show Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Prevalence of Adrenal Insufficiency and Glucocorticoid Use in Pediatric Pseudotumor Cerebri Syndrome Alfonso Hoyos-Martinez, MD, Vincent E. Horne, MD, Alexis C. Wood, PhD, Veeral Shah, MD, PhD Background: The pathophysiology underlying pseudotumor cerebri syndrome (PTCS) is complex and not well understood. There are clear differences between PTCS in adults and pediatrics. Few and isolated case reports have suggested that adrenal function may be involved, yet no large cohort study has examined this relationship. Methods: We conducted a retrospective single-center study of children who presented with a diagnosis of PTCS and had cortisol testing measured between January 2010 and September 2019. We included all subjects meeting the revised PTCS diagnostic criteria after the chart review. Based on morning, random or 1-mg cosyntropin stimulated cortisol levels, adrenal functioning was classified as: (1) insufficient (peak cortisol ,16 mg/dL and AM cortisol ,5 mg/dL), (2) at risk (peak cortisol 16–20 mg/dL, AM cortisol 5–13 mg/dL, or random ,13 mg/dL), or (3) sufficient (peak cortisol .20 mg/dL and AM or random cortisol .13 mg/dL). Results: A total of 398 individuals were reviewed, and 64 were included for analysis. Of these, 40.6% were men, of mixed race and ethnicity with a mean age of 10.5 (SD 4.7) years. Of these, 23% and 52% had insufficient or at-risk cortisol levels. The majority of those in the insufficient (70%) or at-risk (80%) groups were exposed to topical, nasal, or inhaled glucocorticoids but not systemic. Only 60% and 12% of those with PTCS with insufficient or at-risk cortisol testing, respectively, underwent definitive testing with a stimulation test. Conclusions: Glucocorticoid use and hypocortisolism are prevalent in PTCS and need consideration as a potential underlying cause. Most children had insufficient or at-risk Department of Pediatrics, Section of Pediatric Diabetes and Endocrinology (AH-M, VEH), Baylor College of Medicine j Texas Children’s Hospital, Houston, Texas; USDA/ARS Children’s Nutrition Research Center (ACW), Houston, Texas; Department of Ophthalmology (VS), Baylor College of Medicine, Houston, Texas; Cincinnati Children’s Hospital Medical Center (VS), Abrahamson Pediatric Eye Institute/Division of Pediatric Ophthalmology, Cincinnati, Ohio; and Department of Ophthalmology (VS), University of Cincinnati, Cincinnati, Ohio. The authors report no conflicts of interest. Address correspondence to Veeral Shah, MD, PhD, Cincinnati Children’s Hospital Medical Center, Abrahamson Pediatric Eye Institute/Division of Pediatric Ophthalmology, 3333 Burnet Avenue, MLC 7003, Cincinnati, OH 45229-3039 E; E-mail: Veeral.Shah@ cchmc.org Hoyos-Martinez et al: J Neuro-Ophthalmol 2021; 41: e451-e457 cortisol levels, and many did not undergo further testing/ workup. Children who present with PTCS, particularly young, males should be evaluated for adrenal insufficiency and its risk factors, including nonsystemic steroids. Prospective studies are necessary to further evaluate the effect of cortisol in relation to pediatric PTCS. Journal of Neuro-Ophthalmology 2021;41:e451–e457 doi: 10.1097/WNO.0000000000001111 © 2020 by North American Neuro-Ophthalmology Society P seudotumor cerebri syndrome (PTCS), also known as idiopathic intracranial hypertension, is a neurological condition characterized by elevated intracranial pressure (ICP) with normal cerebrospinal fluid (CSF) composition and neuroimaging (1). Primary PTCS refers to elevated ICP where the cause is unknown or idiopathic in nature, whereas, secondary PTCS refers to elevated ICP as a direct result of a medication or medical condition (1). The hallmark ocular finding of PTCS is papilledema or optic nerve edema with elevated ICP, and if left untreated can lead to severe bilateral vision loss (2–4). The incidence in the general population is estimated to be approximately 1 in 100,000 annually in the United States (5). Although there is less data for the pediatric population, the rates are known to be lower with a reported overall incidence of 0.71 per 100,000 annually, with clear increases with age, nearing adult numbers during adolescence (6,7). Although there are similarities in pediatric and adult PTCS for ocular findings and treatment, there are clear clinical differences between these 2 groups (8). In both adults and adolescents, female sex and obesity are strongly associated with PTCS. However, younger prepubertal children have a more equal sex distribution and are less likely to be obese (9–12). Previous studies also describe that prepubertal children are more likely to have an identifiable associated condition, such as medications or respiratory infections, when compared with their adult counterpart e451 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution (13,14), suggesting a different underlying mechanism in young children vs. adolescent and adult subpopulations. The first reports of PTCS date back to late 19th and beginnings of the 20th centuries when patients presented with clear signs and symptoms of elevated ICP (i.e., headache, nausea, diplopia, or vision loss) in the absence of space-occupying lesions (15,16), whereas exogenous corticosteroids were first proposed for clinical use in the 1950’s (17). Shortly thereafter, it was recognized that there was a link between pediatric PTCS and the hypothalamic–pituitary–adrenal (HPA) axis, after 3 children presented with PTCS after steroid withdrawal (18). By 1963, over 10 more case studies had been published of symptoms of PTCS occurring in children being treated with systemic glucocorticoids (GC), many of which arose as the dosage was reduced. This linkage led to the observation that “the occurrence of this condition was quite a rarity until the use of steroids became commonplace” (19). Since then, and during the past decades, sporadic case reports of PTCS after adrenal insufficiency (AI) secondary to Addisonian crises, treatment for Cushing’s disease, or steroid withdrawal have continued to emerge in both pediatric and adult medical literature (20–28). Despite longstanding reports, data regarding the association between AI or hypocortisolism and PTCS remains sparse. Interestingly, high-dose GC have been used as a therapeutic option in treating acute and fulminant PTCS with severe visual impairment (29,30); however, the exact mechanism through which they benefit these patients has not yet been elucidated nor has been the integrity of their adrenal function. AI is a potentially life-threatening condition resulting from adrenal gland disease or adrenocorticotropic hormone (ACTH) deficiency, which often presents with insidious symptoms leading to prolonged and unrecognized disease states until it becomes clinically relevant (31). In pediatrics, by far, the most common cause of AI is decreased secretion of ACTH from the pituitary secondary to prolonged exposure to exogenous GC (31). Approximately 1%–2% of the general adult population report using oral GC (32). The use of these medications is likely higher in children, in light of the higher prevalence of asthma and other atopic conditions in which GC are commonly used (33–35). Moreover, their use in the pediatric population is wide ranging and increasing (36). Considering the serious and potentially irreversible visual and neurological deficits arising from PTCS, and the common use of GC in pediatrics, the lack of knowledge of the association between this condition and AI is concerning. The aim of this study was to describe the prevalence and clinical features of AI and GC use in a PTCS cohort at a large pediatric center. METHODS The study was performed in compliance with all national and institutional regulations. It was reviewed and approved e452 by the Baylor College of Medicine Institutional Review Board (H-38264). A single-center, retrospective cohort study was designed in a large referral pediatric center. Based on ICD-10 diagnostic codes, all children with a diagnosis of PTCS/IIH between January 2010 and September 2019 and an available cortisol level were selected from the institutions’ electronic medical records. A manual chart review was conducted, and relevant information was extracted including clinical data and body mass index (BMI) as z-scores (zBMI) calculated based on Centers for Disease Control and Prevention (CDC) growth chart data matched for age and sex per CDC growth charts (37–39). Children with incomplete records, a central nervous system space-occupying lesion on imaging studies, an associated condition known to cause increased ICP, or misdiagnosis of PTCS were excluded from the final sample. A subject was deemed as misdiagnosed on review of the clinical history, fundus examination and opening pressures on lumbar puncture, using the revised PTCS criteria by a neuro-ophthalmology service (VS) (1). When more than one cortisol test was available, priority was given to the one closest to the diagnosis of PTCS. At the same time, we prioritized results from a 1mg cosyntropin stimulation test (peak level) over a morning (8 AM), over a random level. Based on the cortisol level, subjects were classified into 3 groups as follows: (1) insufficient if peak stimulated cortisol ,16 mg/dL or AM cortisol ,5 mg/dL; (2) at-risk if peak stimulated cortisol 16–20 mg/dL, AM cortisol 5–13 mg/dL, or random ,13 mg/dL; or (3) sufficient peak stimulated cortisol .20 mg/dL or AM or random cortisol .13 mg/dl. A cortisol cut-off level of 16 mg/dL for the 1-mcg cosyntropin test was used because this displays higher specificity in diagnosing secondary AI when compared with 18 mg/dL (40). A subject was considered to have a history of prolonged use of steroids if GC use for more than 2 weeks was recorded, preceding the diagnosis of PTCS. Route of administration for the documented medications was reported and classified as: (1) systemic if injectable or oral; (2) nonsystemic if intranasal, topical, or inhaled; and (3) mixed if used concomitantly, that is, topical and oral. Statistical Analysis Analyses were conducted in R v. 3.5.0 (41). Descriptive statistics (mean ± SD for continuous variables and percentages for categorical variables) are presented stratified by the cortisol test result (sufficient/at-risk/insufficient; Table 1). One sample z-tests were used to examine whether the proportions of each possible cortisol test differed from the other proportion (e.g., to test whether there were more with sufficient vs at-risk results, a 1-sided z-tests tested whether these 2 proportions could be equated). Univariable analyses used 2-sample z-tests (categorical variables) or t-tests (continuous variables) to compare demographic variables, medical histories, and information on cortisol testing between Hoyos-Martinez et al: J Neuro-Ophthalmol 2021; 41: e451-e457 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Sample characteristics by groups of adrenal function tests Interpretation of the Cortisol Test, (%) Characteristic Age at diagnosis, years Mean (SD) Sex Female Male Race/Ethnicity African American Asian Hispanic White Non-Hispanic White BMI, z-score Mean (SD) History of asthma Yes No History of prolong use of steroids Yes No Steroids route Nonsystemic alone Systemic alone Mixed Concomitant pituitary deficiencies Yes No Symptoms of increased ICP Yes No Cortisol test AM Random ACTH stimulation Time to PTCS diagnosis Days, mean (SD) Time relative to diagnosis Before Same day After Treatment with glucocorticoids Yes No Treatment with acetazolamide Yes No Sufficient (n = 16) At-Risk (n = 33) Insufficient (n = 15) 11.1 (4.0) 11.2 (5.2) 9.9 (4.8) 13 (81.2)C 3 (18.8) 20 (60.6) 13 (39.4) 5 (33.3) 10 (66.7)A 2 (12.5) 1 (6.2) 2 (12.5) 11 (68.8) 9 (27.3) 2 (6.1) 5 (15.2) 17 (51.5) 1 (6.7) 3 (20) 11 (73.3) 1.7 (0.9) 1.3 (1.4) 0.9 (1.5) 2 (12.5) 14 (87.5)A 6 (18.2) 27 (81.8)A 8 (53.3)B,C 7 (46.7) 7 (43.8)A 8 (56.2) 5 (15.2) 28 (84.8)A,C 10 (66.7)B 5 (33.3) 4 (57.1) 2 (28.6) 1 (14.3) 4 (80) — 1 (20) 7 (70) 2 (20) 1 (10) 1 (93.8) 15 (6.2) — 33 (100) 1 (93.3) 14 (6.7) 15 (93.8) 1 (6.2) 29 (87.9) 4 (12.1) 12 (80) 3 (20) 5 (31.2) 4 (25) 7 (43.8)B 14 (42.4) 16 (48.5) 3 (9.1) 6 (40) 9 (60)B 0.4 (1.7) 0.4 (0.7) 1.5 (3.3) 4 (25) 1 (6.2) 11 (68.8) 7 (21.2) 1 (3.0) 25 (75.8) 2 (13.3) — 13 (86.7) 4 (25) 12 (75)C 2 (6.1) 31 (93.9)C 9 (60)A,B 6 (40) 15 (100) — 31 (93.9) 2 (6.1) 15 (100) — Letters A (sufficient), B (at-risk), and C (insufficient) denote statistically significant difference (P = , 0.05) between groups. ACTH, adrenocorticotropic hormone; ICP, intracranial pressure; PTCS, pseudotumor cerebri syndrome. the groups. Observing the small sample size, exploratory multivariable models were run using penalized logistic regression, specifying cortisol test result as the outcome (as a 3-category definition), race/ethnicity, age, zBMI, and time between IIH diagnosis and cortisol testing as covariates. The following variables were run as predictors in separate models: (1) male sex, and—with sex as an additional covariate—(2) prolonged history of any steroid use, (3) Hoyos-Martinez et al: J Neuro-Ophthalmol 2021; 41: e451-e457 prolonged history of only nonsystemic steroid use, and (4) history of asthma. In all cases, significance was set at P , 0.05. RESULTS This study cohort was assembled from 398 unique records of children carrying a diagnostic code for PTCS, after reviewing the medical records of those with an e453 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution inappropriate diagnosis were excluded (334). The subjects included (n = 64) had mixed race and ethnicity, a mean age of 11.5 (SD ± 4.7) years, and 59% were women (Table 1). In the study population, 23%, 52%, and 25% were deemed to have insufficient, at-risk, and sufficient cortisol test results, respectively (Table 1). Most of the patients (67%) in the insufficient group had been on GC preceding the diagnosis of PTCS. Of those exposed, most had been on noninjectable or enteral formulations of these medications. Dynamic testing with cosyntropin stimulation test was performed in 60% and 9% of those in the insufficient and atrisk groups, respectively. Other medications known to be associated with PTCS, such as progestins, tetracyclines, or retinoids were identified in 8 patients, but only in 1 case was this medication deemed by the treating physician to be responsible for the PTCS by the chart review. This was a subject in the insufficient group who was exposed to megestrol acetate, which is known to lead to suppression of the HPA axis (42). As we have previously reported, once megestrol was discontinued and physiologic corticosteroid hormonal replacement was started, papilledema and PTCS symptoms resolved shortly after (43). Univariable Analyses No differences in age or body composition were seen among groups. However, those with insufficient cortisol were more likely to be men and had a history of asthma, when compared with those with normal and at-risk HPA axis function (P = , 0.05). Multivariable Analyses Concurrently, exploratory multivariable analysis controlling for age, race, zBMI, and time between cortisol test and PTCS diagnosis suggested that men were more likely to have an insufficient cortisol test when compared with the atrisk group (P = , 0.001) but not when compared against the sufficient group. Similarly, those with insufficient cortisol test results were more likely to have a history of asthma when compared with those in the at-risk (P = , 0.001) and normal (P = , 0.001) groups. Prolonged exposure to steroids was associated with cortisol test results when comparing the insufficient to the at-risk group (P = , 0.001), and insufficient to the sufficient group (P = 0.028) but not when comparing the at-risk and sufficient groups. CONCLUSIONS We found that hypocortisolism and GC use was prevalent in children with PTCS, and to the best of our knowledge, this is the only cohort study to examine the distribution of adrenal function in pediatric PTCS. Male sex was observed to decrease the chances of having normal adrenal testing; this was partially replicated on the multivariate model providing 2 lines of evidence that in fact sex, but none of the other demographic or anthropometric measures play a e454 significant role. The main characteristics associated with PTCS in adults and adolescents are female sex and overweight or obesity. However, in young children, neither sex nor body composition seem to be as clinically relevant (9–12), and presumably an underlying comorbid condition is more likely a factor (13,14). In our cohort, men had a greater chance of having abnormal cortisol levels, regardless of BMI. Thus, young, nonobese, male patients with PTCS, who do not follow the typical clinical profile for PTCS, may have AI as an underlying condition. The prolonged use of GC was elevated in our cohort with over a third of the children having been exposed to various forms of these drugs. Even more striking, most of these medications were given through topical, intranasal, or inhaled routes not systemic (enteral or injectable). A reminder, that ACTH-suppressing effect is not exclusive to systemic GC use. Inhaled GC use, even at therapeutic dosages, can lead to AI, particularly in subjects with low BMI, concomitant nasal GC use, or with cumulative doses (44). Consequently, HPA axis suppression in children with asthma using inhaled steroids can occur in up to two-thirds of this population (45). Similarly, prolonged use of transdermal GC, particularly high-potency, may also result in AI (46). Moreover, children are particularly susceptible to HPA axis suppression because of their increased absorption from thinner skin and greater surface area to weight ratio (47). Given that over a third of our cohort had documented, prolonged GC exposure, it is reasonable to contemplate AI may be associated with the development of PTCS in at least some of these patients. Periods of hypocortisolism resulting from intermittent GC use, as seen in perennial atopic conditions, may result in PTCS in children prone to AI. Such a cause–effect relation is also supported by PTCS cases related to GC use in children with atopic conditions (22,43). Notably asthma, but not GC exposure, was associated with abnormal cortisol function testing and could be due to under-documentation of the usage of these medications. GC use is highly prevalent in patients with asthma, not only in their inhaled forms, but also intranasal and topical for frequently coexisting conditions such as allergic rhinitis and eczema (35,48). Furthermore, a number of GCs are easily available over the counter, particularly in topical and intranasal forms directed to treat these conditions. Agraz et al (49) found an elevated prevalence of respiratory allergies in a pediatric PTCS cohort, proposing a role for autoimmunity in abnormal CSF flow. By contrast, our data would suggest that such high rates of allergies and atopic conditions in pediatric PTCS (49) correlate with GC use (34). This along with childhood susceptibility to AI (45,47) presumably causes PTCS development not the immune system directly. In addition, in our cohort, we identified a case of AI secondary to the use of megestrol acetate, a progestin analogue. This medication is known to reversibly suppress the HPA axis by direct stimulation at the GC receptor Hoyos-Martinez et al: J Neuro-Ophthalmol 2021; 41: e451-e457 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution (42,43). Thus, the role of the HPA axis in the development of PTCS may not be inherent to GC medications, but any other factor leading to AI may have a similar outcome. Although the association between AI and PTCS was first described in the midst of the 20th century (18), to date the neuroendocrine interaction between the HPA axis and CSF physiology remains unclear. Interestingly, the choroid plexus epithelial cells responsible for CSF production, avidly express the mineralocorticoid receptor (MR), which is activated by both aldosterone and GC (50). This receptor along with the action of the 11b-dehydrogenase enzyme seems to exert a key role in CSF and ICP regulation (51). Salpietro et al (52) hypothesize that a state of AI may decrease MR activation, ultimately leading to a reduction of CSF absorption in the arachnoid villi and an increase in resistance to CSF outflow, causing PTCS. Such decreased absorption has also been demonstrated in dogs (53) and by radioisotope cisternography (54). Likewise, an increase in MR activation during hypotension because of adrenal crises or relative states of hypocortisolism could increase the intraventricular osmotic gradient, potentially elevating the ICP (51). This proposed mechanism is strengthened by the successful use of spironolactone in acetazolamide-unresponsive PTCS in children (55). As well, our personal clinical experience at our center has shown that some children diagnosed with PTCS concomitantly have AI and exhibit clinical improvement once they start physiologic GC replacement (unpublished data) (43). The limitations of our study are inherent to the retrospective nature of the design, considering that the temporality between GC exposure, adrenal function testing, and PTCS is considerable. Although the population of our study is arguably small, considering the rarity of this pathology in pediatrics, it is in fact quite sizeable because other studies were limited to case reports or small case series. However, power may still not be sufficient to disclose any conflated associations. This became particularly evident during multivariate analysis. Diagnostic testing for AI has inherent limitations, including the appropriate threshold value to make the diagnosis, adherence to the standardization of blood sample drawing and processing, diurnal variation, and appropriate administration of cosyntropin during stimulation testing. Nonetheless, for this study, we were more stringent than our locally accepted threshold values for the diagnosis of AI, using a lower threshold for diagnosis resulting in higher test specificity (40). In addition, we examined our data using a higher cortisol threshold for the cosyntropin stimulation tests of 18 mg/dL, without discernible differences among groups. Despite only including subjects with a diagnosis of PTCS and an available cortisol level, there was an alarmingly high prevalence of prolonged exposure to GC and abnormal adrenal testing. This is considerably higher Hoyos-Martinez et al: J Neuro-Ophthalmol 2021; 41: e451-e457 than the general population, who have an estimated prevalence of secondary AI of only 150–280 per million in adults (56). In addition, we believe cortisol assessment was often obtained for concerns of hypercortisolism and not AI; this is supported by the lack of further testing in over two-thirds of the studied population and the temporality of the tests in relation to the diagnosis of PTCS. The real dimension of these findings may not be truly accurate and so, multicentric, prospective studies are in need. In summary, we present a pediatric PTCS cohort with a high prevalence of abnormal cortisol testing, and a high frequency of GC exposure, predisposing to abnormal HPA axis function. Most children with prolonged use of GC were on nonsystemic forms. Children with PTCS, particularly, young, male, and nonobese, should be evaluated conscientiously for AI and factors predisposing to it. Finally, we observe with concern that cosyntropin stimulation testing was seldom performed, even in patients with insufficient or at-risk cortisol testing or those with known risk factors. AI in children is often unrecognized until illness occurs, and thus, a heightened level of suspicion is needed to identify and treat timely to avoid possibly fatal outcomes. In the case of PTCS, treating underlying AI, when present, may possibly alleviate its course. Prospective and multicenter studies are needed to further establish and define the role of the HPA axis in pediatric PTCS. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. Hoyos-Martinez, V. Shah, and V. E. Horne; b. Acquisition of data: A. Hoyos-Martinez, V. Shah, and V. E. Horne; c. Analysis and interpretation of data: A. C. Wood, A. Hoyos-Martinez, V. Shah, and V. E. Horne. Category 2: a. Drafting the manuscript: A. C. Wood, A. Hoyos-Martinez, V. Shah, and V. E. Horne; b. Revising it for intellectual content: A. C. 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Date | 2021-12 |
Language | eng |
Format | application/pdf |
Type | Text |
Publication Type | Journal Article |
Source | Journal of Neuro-Ophthalmology, December 2021, Volume 41, Issue 4 |
Publisher | Lippincott, Williams & Wilkins |
Holding Institution | Spencer S. Eccles Health Sciences Library, University of Utah, 10 N 1900 E SLC, UT 84112-5890 |
Rights Management | © North American Neuro-Ophthalmology Society |
ARK | ark:/87278/s6zf9zyr |
Setname | ehsl_novel_jno |
ID | 2116184 |
Reference URL | https://collections.lib.utah.edu/ark:/87278/s6zf9zyr |