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  1. Eleni Papakokkinou, Marta Piasecka, Hanne Krage Carlsen, Dimitrios Chantzichristos, Daniel S. Olsson, Per Dahlqvist, Maria Petersson, Katarina Berinder, Sophie Bensing, Charlotte Höybye, Britt Edén Engström, Pia Burman, Cecilia Follin, David Petranek, Eva Marie Erfurth, Jeanette Wahlberg, Bertil Ekman, Anna-Karin Åkerman, Erik Schwarcz, Gudmundur Johannsson, Henrik Falhammar & Oskar Ragnarsson Abstract Purpose Bilateral adrenalectomy (BA) still plays an important role in the management of Cushing's disease (CD). Nelson’s syndrome (NS) is a severe complication of BA, but conflicting data on its prevalence and predicting factors have been reported. The aim of this study was to determine the prevalence of NS, and identify factors associated with its development. Data sources Systematic literature search in four databases. Study Selection Observational studies reporting the prevalence of NS after BA in adult patients with CD. Data extraction Data extraction and risk of bias assessment were performed by three independent investigators. Data synthesis Thirty-six studies, with a total of 1316 CD patients treated with BA, were included for the primary outcome. Pooled prevalence of NS was 26% (95% CI 22–31%), with moderate to high heterogeneity (I2 67%, P < 0.01). The time from BA to NS varied from 2 months to 39 years. The prevalence of NS in the most recently published studies, where magnet resonance imaging was used, was 38% (95% CI 27–50%). The prevalence of treatment for NS was 21% (95% CI 18–26%). Relative risk for NS was not significantly affected by prior pituitary radiotherapy [0.9 (95% CI 0.5–1.6)] or pituitary surgery [0.6 (95% CI 0.4–1.0)]. Conclusions Every fourth patient with CD treated with BA develops NS, and every fifth patient requires pituitary-specific treatment. The risk of NS may persist for up to four decades after BA. Life-long follow-up is essential for early detection and adequate treatment of NS. Introduction Cushing´s disease (CD) is a rare disorder associated with excess morbidity and increased mortality [1, 2]. Previously, bilateral adrenalectomy (BA) was the mainstay treatment for CD. During the last decades, however, other treatment modalities have emerged, including pituitary surgery, radiotherapy and medical treatments. Despite this, BA is still considered when other treatment options have failed to achieve remission, or when a rapid relief of hypercortisolism is necessary [3]. BA is considered to be a safe and effective treatment for CD [4], especially after the laparoscopic approach was introduced during the 1990s [5]. There are, however, significant drawbacks with BA, mainly the unavoidable chronic adrenal insufficiency, as well as the risk for Nelson’s syndrome (NS), i.e., growth of the remaining pituitary tumor and excessive production of ACTH, that may cause optic nerve or chiasmal compression and mucocutaneous hyperpigmentation [6]. The prevalence of NS varies between studies, mainly due to a lack of consensus on the definition and diagnostic criteria for the syndrome [7, 8]. Previously published studies are also inconsistent as to whether factors such as previous radiotherapy, age at BA, gender and duration of CD, may affect the risk of developing NS. Furthermore, high ACTH concentrations after BA have been suggested as a risk factor for developing NS [9,10,11,12]. Thus, the primary aim of this systematic review and meta-analysis was to estimate the prevalence of NS after BA for CD, both the total prevalence of NS as well the prevalence of NS requiring treatment with pituitary surgery and/or radiotherapy. The secondary aim was to investigate risk factors associated with development of NS. Methods A systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [13]. The PICO process was applied for the definition of the research question and eligibility criteria for the literature search. The protocol of this review was registered in the PROSPERO database (CRD42020163918). Search strategy We searched PubMed, Embase, Cochrane Library and Web of Science on February 25th 2020, with no start date restriction, for relevant articles by using the following terms: “Cushing´s syndrome” or “Cushing´s disease” or “Hypercortisolism” or “Pituitary ACTH hypersecretion” or “corticotroph tumor” or “corticotroph tumors” or “corticotroph adenoma” or “corticotroph adenomas” or “corticotropinoma” or “corticotropinomas” or “corticotrophinoma” or “corticotrophinomas” or “ACTH pituitary adenoma” or “ACTH pituitary adenomas” or “adrenocorticotropin pituitary adenoma” or “adrenocorticotropin pituitary adenomas” AND “bilateral adrenalectomy” or “bilateral adrenalectomies” or “total adrenalectomy” or “total adrenalectomies”. A detailed description of the search strategy is given in the Supplementary. Also, references of the included studies and relevant review articles were checked manually for additional articles. A new search was performed on January 12th 2021, prior submission, to identify any new publications. Study selection and eligibility criteria Eligible studies were observational studies (cohort or cross-sectional studies) reporting the prevalence of NS in adult patients with CD treated with BA. Studies including only children (age < 18 years), review articles, letters, commentaries and meeting abstracts were excluded. Moreover, case reports, case-series and studies with a population of fewer than 10 cases were excluded. Also, studies written in languages other than English were not considered for inclusion. Data collection process and data extraction Titles and abstracts from all identified articles were screened for eligibility and further full-text assessment by three independent investigators (EP, MP, OR). Discrepancies were resolved through discussion and consensus. Duplicate articles and studies with overlapping populations were excluded. In the latter case, the publication with the largest population, more comprehensive information on relevant clinical variables and/or lowest risk of bias was included. Full-text assessment and data extraction were conducted independently by the same investigators as above. Data on the following predefined variables were extracted: first author, year of publication, region/hospital, study period, characteristics of the study population (number of patients, gender, follow-up, age at CD, age at BA, previous treatment with radiotherapy and/or pituitary surgery, ACTH concentrations at BA, MRI findings at CD and at BA), intervention (BA as primary or secondary treatment, remission status) and outcome (criteria for NS, number of patients with NS, age at NS, time from BA to NS, ACTH concentrations one year after BA, number of patients treated for NS, type of treatment; pituitary radiotherapy and/or pituitary surgery). One of the studies included in the meta-analysis is our nationwide Swedish study on CD [2]. Additional clinical data, not provided in the original publication, was retrieved and used in the current analysis (Table 1). Table 1 Characteristics of the included studies Full size table Risk of bias assessment The Newcastle–Ottawa Scale [14], modified to suit the current study, was used for assessment of risk of bias of all included studies. Three investigators (EP, MP, OR) assessed the studies independently, and any disagreements were resolved by discussion. Selection, comparability and outcome were assessed through predefined criteria. All studies that provided information on NS as outcome, and/or corticotroph tumor progression, were included, and the definition as well as the treatment of NS were recorded (Table 1 and Table S1). A clear definition of NS and information on treatment were considered to be two of the most important components of the quality assessment. We considered the definition of NS to be clear when it included either a new visible pituitary tumor or progression of a pituitary tumor remnant following BA, alone, or in combination with high ACTH concentrations and/or hyperpigmentation. Detailed description of the criteria for the risk of bias assessment is provided in the Supplementary file. Studies with an overall score ≥ 5 (max overall grade 😎 and a clear definition of NS, were considered to have a low risk of bias. Data synthesis and statistical analysis Primary endpoints were the prevalence of NS, as well as the prevalence of pituitary-specific treatment for NS. Descriptive data are presented as median (range or interquartile range; IQR). Meta-analysis was performed by using the meta package in R (version 4.0.3) [15]. Statistical pooling was performed according to random-effects model due to the clinical heterogeneity among the included studies [16]. For all analyses, indices of heterogeneity, I2 statistics and Cochrane’s Q test, are reported. For the primary outcomes we estimated pooled prevalence with 95% confidence intervals (95% CI). Statistical significance was defined as P < 0.05. The possibility of publication bias was assessed by visual inspection of funnel plots as well as with the Egger’s test [17]. Sensitivity analyses were performed by excluding studies with an overall risk of bias < 5, and studies where information on diagnostic criteria for NS was lacking. By choosing the overall risk of bias < 5, all studies without adequate follow-up were also excluded (Table S2). Also, another sensitivity analysis was performed by including all studies reporting the number of patients with NS who received treatment for NS (Table 1). Subgroup analyses were performed to investigate factors that may affect the prevalence of NS, namely pituitary radiotherapy prior to BA, prophylactic pituitary radiotherapy, overall radiotherapy (prior to BA or prophylactic), pituitary surgery (transcranial or transsphenoidal surgery) prior to BA, and BA as primary or secondary treatment. For these outcomes, we estimated relative risks (RRs), or pooled prevalence, with 95% CIs. Also, in a subgroup analysis, the prevalence (with 95% CI) of NS and treatment for NS were estimated in studies where MRI was used at diagnosis and during follow-up. Uni- and bivariate meta-regression was used to investigate whether the prevalence of NS was influenced by median follow-up time or age at BA. The meta-analysis was performed by using the Metareg command in R. The estimated association is reported as β coefficient. Role of funding source The funding source had no role in the design and conduction of the study; i.e., collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Results Identification and description of included studies After removal of duplicates, 1702 articles were identified (Fig. 1). Three additional articles were found after checking the reference lists of identified articles and review papers. After reviewing titles, abstracts and full-text articles, 48 articles were considered eligible for further analysis. Of these, however, 11 articles were excluded due to overlapping or identical patient cohorts. Thus, 37 studies published between 1976 and 2020, were included in the current meta-analysis (Fig. 1). All studies had a retrospective observational design. Characteristics of the included studies are presented in Table 1. Two of the included studies had an overlapping cohort where one was used for the main outcome [18] and one [19] for the subgroup analyses on the influence of radiotherapy on the development of NS. An overview of risk of bias assessment of the eligible studies is provided in Table S2. Fig. 1 Flowchart of study selection Full size image In total, 1316 patients with CD treated with BA were included. The median follow-up after BA was 7 years (23 studies, range 3.3–22). Median age at BA in patients with NS was 31 years (13 studies, IQR 26–34). Median time from BA to the diagnosis of NS was 4 years (19 studies) with the shortest reported time being 2 months [20] and the longest 39 years [2]. At diagnosis of NS, hyperpigmentation was reported in 155 of 188 (82%) patients (19 studies) and chiasmal compression in 24 of 129 (19%) patients [11 studies]. Prevalence of NS Thirty-six of 37 studies, with total 1316 patients with CD treated with BA, were included [2, 18, 20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53]. Reported prevalence of NS ranged from 4 to 60%. The mean pooled prevalence was 26% (95% CI 22–31%) with a moderate to high heterogeneity (I2 67%, P < 0.01) (Fig. 2). The Egger’s test was statistically significant (P = 0.01), but visual inspection showed no obvious asymmetry. The significant Egger’s test indicates publication bias, probably explained by the fact that case reports and cohorts with fewer than 10 participants were excluded (Fig. S1). Fig. 2 Forest plot showing individual studies and pooled prevalence of Nelson’s syndrome after bilateral adrenalectomy in patients with Cushing’s disease. *Additional data Full size image In a sensitivity analysis, excluding all studies with high risk of bias (overall score < 5) and no clear definition of NS, the pooled prevalence was 31% (95% CI 24–38%; I2 76%, 17 studies, 822 patients; P < 0.01) (Fig. S2). In a subgroup analysis, the prevalence of NS in studies where MRI was used at diagnosis and during follow-up was 38% (Fig. 3; 95% CI 27–50%; I2 71%, 7 studies, 280 patients; P < 0.01). Fig. 3 Forest plot showing individual studies using magnetic resonance imaging and pooled prevalence of Nelson’s syndrome after bilateral adrenalectomy in patients with Cushing’s disease Full size image Prevalence of treated NS The pooled prevalence of treatment for NS was 21% (95% CI 18–26%; I2 52%, P < 0.01) (Table 1; 29 studies with 1074 patients). Thus, the pooled prevalence was slightly lower, compared to the pooled prevalence of NS in total, as well as the heterogeneity (Fig. S3). The funnel plot showed no asymmetry and Egger’s test was not statistically significant, indicating low possibility of publication bias (Fig. S4). In a subgroup analysis, the prevalence of treated NS in studies where MRI was used at diagnosis and during follow-up was 25% (95% CI 17–35%; I2 61%, 7 studies; P = 0.02). The indication for treatment was progression of the pituitary tumor in 23 out of 28 patients (82%, five studies), optic chiasmal compression in 11 out of 91 patients (12%, 11 studies), while four patients out of 14 (one study) had both these indications for treatment. Twenty-six studies provided information on treatment modalities (pituitary surgery and/or radiotherapy). Seventy-three out of 201 patients with NS (36%) were treated with pituitary surgery, 86 (43%) with radiotherapy and 41 (20%) received both treatments. Radiotherapy Nineteen studies provided information on radiotherapy prior to BA. However, nine studies had no events and no patients in one of the arms (radiotherapy or no radiotherapy) (Table S3). Thus, ten studies were eligible for further estimation, showing that the risk for NS in patients treated with radiotherapy prior to BA was comparable to the risk in patients not treated with radiotherapy (RR 0.9, 95% CI 0.5–1.6; 10 studies with 564 patients) (Fig. 4). Fig. 4 Forest plot showing the RR (relative risk) and 95% CI for Nelson’s syndrome in patients treated with radiotherapy prior to bilateral adrenalectomy versus no radiotherapy. RR could not be calculated when there were no cases in the RTX or no RTX arms, and when no events in either arm. *Additional data. RTX, radiotherapy prior to bilateral adrenalectomy or prophylactic radiotherapy Full size image Thirteen studies provided information on prophylactic radiotherapy. However, only one study provided applicable data for calculating RR, thus subgroup analysis was not performed (Table S4). In that study [20], none of the seventeen patients who received prophylactic radiotherapy developed NS, while 11 of 22 patients without radiotherapy developed NS after a mean follow-up of 4.4 years (range 10–16 years). By using studies with information on either previous or prophylactic radiotherapy (11 studies with 603 patients; Table S5), the pooled RR was 0.8 (95% CI 0.5–1.5). Pituitary surgery prior to BA Of 21 studies with information on pituitary surgery prior to BA (Table S6), only ten provided information for estimation of RR. A pooled RR of 0.6 (10 studies with 430 patients; 95% CI 0.4–1.0) was found (Fig. 5), indicating that the risk for developing NS was not influenced by previous pituitary surgery. Fig. 5 Forest plot showing the RR (relative risk) and 95% CI for Nelson’s syndrome in patients treated with pituitary surgery prior to bilateral adrenalectomy versus no pituitary surgery. RR could not be calculated when there were no cases in the surgery or no surgery arms, and when no events in either arm. *additional data. Abbreviations: Surgery, pituitary surgery prior to bilateral adrenalectomy Full size image BA as primary or secondary treatment for CD Information on whether patients with NS were treated primarily with BA or not, was provided in ten and nine studies, respectively (Fig. S5 and S6). The pooled prevalence of NS was 26% (95% CI 20–33%) for patients treated primarily with BA and 22% (95% CI 15–31%) for patients who had been treated with pituitary surgery and/or radiotherapy prior to BA. ACTH concentrations one year after BA Four studies provided information on ACTH concentrations during the first year after BA [45, 49, 52, 53]. In a study by Assié et al. the median ACTH concentration in patients who developed NS was 301 pmol/L, compared to 79 pmol/L in patients without NS (upper range of limit; URL 13 pmol/L) [52]. The median ACTH concentration in a study by Cohen et al. was 105 pmol/L in the NS group compared to 18 pmol/L in patients without NS (P = 0.007) (URL 10 pmol/L) [49]. Also, in a study by Das et al., there was a statistically significant difference in ACTH concentrations one year after BA between patients with and without NS (110 vs 21 pmol/L respectively; P = 0.002) [53]. On the contrary, Espinosa-de-Los-Monteros et al.found no difference in ACTH concentrations between the patients with NS and those without NS [45]. Thus, three of four studies found that high ACTH concentrations one year after BA were associated with the development of NS. However, since the ACTH assays and the conditions when ACTH was collected were different in these studies (Table S7), further comparison or a meta-analysis on ACTH levels after BA was not considered feasible. Influence of age at BA and duration of follow-up on prevalence of NS In a meta-regression analysis, age at BA (β-coefficient = – 0.03, P = 0.4; Fig. 6) and median duration of follow-up (β-coefficient = 0.01, P = 0.7; Fig. S7) were not associated with prevalence of NS. After adjustment for follow-up, age at BA was still not associated with prevalence of NS (β-coefficient = -0.03, P = 0.4). Fig. 6 Bubble plot showing the influence of age at BA on the prevalence of Nelson’s syndrome. The bubble sizes are proportional to the weight of the studies in the meta-analysis. Coefficient estimate (β) and p value for the effect of age at BA are indicated by the regression line Full size image Discussion In this study we have for the first time evaluated the pooled prevalence of NS by using a meta-analysis on data from 36 studies, including more than 1300 patients with CD treated with BA. The overall prevalence of NS was 26% and the median time from BA to diagnosis of NS was 4 years, ranging from 0.2 to 39 years. The prevalence of patients requiring pituitary-specific treatment for NS was 21%. Furthermore, radiotherapy and pituitary surgery prior to BA, as well as age at BA, did not seem to affect the risk of developing NS. Various definitions have been used for NS over the past decades [12]. Historically, the diagnosis was based on clinical findings related to mucocutaneous hyperpigmentation and chiasmal compression, together with signs of an enlarged sella turcica on skull radiography [6]. Since then, the diagnosis of NS in most studies has been based on (i) radiological evidence of a pituitary tumor that becomes visible, or a progression of a preexisting tumor, (ii) “high” ACTH concentrations, and (iii) hyperpigmentation [54]. In the studies with the highest prevalence of NS [45, 46], the diagnosis was based on rising ACTH concentrations and an expanding pituitary mass, where 2 mm increment in tumor size on MRI was considered to be a significant growth. On the contrary, the criteria for NS in studies with the lowest prevalence were based on hyperpigmentation, often but not always combined with a pituitary tumor responding to radiotherapy and/or a radiographic evidence of pituitary tumor on skull radiography [21, 23]. Thus, the great variance in the prevalence of NS between studies can, at least partly, be explained by the different definitions of NS. Consequently, in an expert opinion published in 2010, it was suggested that the diagnosis of NS should be based on an elevated level of ACTH >500 ng/L (110 pmol/L) in addition to rising levels of ACTH on at least three consecutive occasions and/or an expanding pituitary mass on MRI or CT following BA [54]. Similarly, in a recently published expert consensus recommendation, based on a systematic review, it was suggested that NS should be defined as radiological progression or new detection of a pituitary tumor on a thin-section MRI [55]. Furthermore, the authors recommend active surveillance with MRI three months after BA, and every 12 months for the first 3 years, and every 2–4 years thereafter, based on clinical findings. The meta-regression of the current analysis did not show an association between median follow-up time and prevalence of NS. Nevertheless, NS occurred as early as 2 months [20], and up to 39 years after BA [2], supporting that life-long surveillance after BA is necessary for patients with CD. Active surveillance with MRI was more common in studies published during the last two decades. In fact, the use of MRI in recent studies resulted in earlier detection of a growing pituitary adenoma and, subsequently, contributed to a higher prevalence of NS. Namely, the seven studies including patients treated with BA after 1990 and using MRI reported higher prevalence of NS, both overall NS and treated NS. Whether factors such as pituitary radiotherapy affects the risk for development of NS has been evaluated in several studies. Some studies have shown that radiotherapy prior to BA, or administrated prophylactically, can prevent or delay the development of NS [20, 39]. On the contrary, other studies have not demonstrated a protective effect of radiotherapy prior to BA [18, 37] and, moreover, one study found an association with tumor progression [46]. Nevertheless, the current meta-analysis indicates that radiotherapy prior to BA does not decrease the risk of developing NS. Neither did previous pituitary surgery affect the risk for NS. Elevated ACTH concentrations during the first year after BA have been considered to be a strong predictor of NS [49, 52]. In fact, seven studies in the current analysis included cut-off levels for ACTH concentration, arbitrarily defined, for the diagnosis of NS [18, 25, 34, 36, 41, 45, 49]. Due to the different ACTH assays, and different conditions when ACTH was collected, no further analysis on ACTH levels was performed. Nevertheless, four studies [45, 49, 52, 53] reported ACTH concentrations one year after BA in both patients with and without NS. Three of these studies found that high ACTH concentrations one year after BA [49, 52, 53] were associated with pituitary tumor progression. Thus, these findings support the suggestion that ACTH should be monitored following BA in patients with CD [54, 55]. The prevalence of treatment for NS (21%), and the heterogeneity index (52%), were slightly lower than in the analysis of total prevalence of NS (26%, I2 67%). The majority of the patients was treated with radiotherapy, followed by pituitary surgery and combination of pituitary surgery and radiotherapy. Today, surgical removal of the pituitary tumor is considered to be the first-line therapy of NS whereas radiotherapy is considered if surgery has failed or is not possible [12, 54, 56]. In a large multi-center study by Fountas et al., the 10-year progression-free survival rates after surgery alone, or with radiotherapy, for patients with NS was 80% and 81%, respectively [57]. In comparison, progression-free survival rate in patients who did not receive treatment was 51%. Reports on the efficacy of medical therapy for NS have shown inconsistent results [56]. Strengths and limitations This is the largest systematic review, and the first meta-analysis, on NS published to date. However, some limitations have to be acknowledged. Most important are the different diagnostic methods used to detect NS, and the different definitions of the syndrome between the studies. The majority of the studies have used the combination of hyperpigmentation, high ACTH concentrations and radiological findings for the diagnosis of NS. Notwithstanding these common criteria, there were still differences in the cut-offs of ACTH levels, the use of different radiological modalities over time as well as the radiological definition of progress of pituitary tumors. Moreover, in some studies radiological findings were used solely or in combination with either hyperpigmentation and/or bitemporal hemianopsia, ACTH concentrations or response to treatment of NS. Furthermore, in several studies a clear definition of NS was not provided. Nevertheless, we consider our attempt to address the heterogeneity of the included studies, through systematic review, quality assessment, and sensitivity and subgroup analyses to be a strength. Conclusions The risk of NS after BA in patients with CD is considerable and may first become clinically evident many decades later. Thus, life-long close follow-up is necessary for an early detection of a growing pituitary tumor, and adequate treatment when needed. Although this meta-analysis did not find prior surgery or radiotherapy to be associated with risk of NS, the findings are based on a limited number of studies. Thus, in order to individualize the treatment for patients with CD, further studies are needed where these and other factors possibly associated with risk of NS are evaluated. Data availability The data generated or analyzed during this study are included in this published article or in the Supplementary file. Abbreviations CD: Cushing's disease BA: Bilateral adrenalectomy NS: Nelson’s syndrome ACTH: Adrenocorticotropic hormone RR: Relative risk MRI: Magnet resonance imaging CT: Computer tomography References 1. Papakokkinou E, Olsson DS, Chantzichristos D, Dahlqvist P, Segerstedt E, Olsson T, Petersson M, Berinder K, Bensing S, Hoybye C, Eden-Engstrom B, Burman P, Bonelli L, Follin C, Petranek D, Erfurth EM, Wahlberg J, Ekman B, Akerman AK, Schwarcz E, Bryngelsson IL, Johannsson G, Ragnarsson O (2020) Excess morbidity persists in patients with cushing's disease during long-term remission: a swedish nationwide study. J Clin Endocrinol Metab 105(8):2616–2624 2. Ragnarsson O, Olsson DS, Papakokkinou E, Chantzichristos D, Dahlqvist P, Segerstedt E, Olsson T, Petersson M, Berinder K, Bensing S, Hoybye C, Eden-Engstrom B, Burman P, Bonelli L, Follin C, Petranek D, Erfurth EM, Wahlberg J, Ekman B, Akerman AK, Schwarcz E, Bryngelsson IL, Johannsson G (2019) Overall and disease-specific mortality in patients with cushing disease: a swedish nationwide study. J Clin Endocrinol Metab 104(6):2375–2384 PubMed Article Google Scholar 3. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A, Endocrine S (2015) Treatment of cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 100(8):2807–2831 CAS PubMed PubMed Central Article Google Scholar 4. Ritzel K, Beuschlein F, Mickisch A, Osswald A, Schneider HJ, Schopohl J, Reincke M (2013) Clinical review: outcome of bilateral adrenalectomy in Cushing’s syndrome: a systematic review. J Clin Endocrinol Metab 98(10):3939–3948 CAS PubMed Article Google Scholar 5. Reincke M, Ritzel K, Osswald A, Berr C, Stalla G, Hallfeldt K, Reisch N, Schopohl J, Beuschlein F (2015) A critical reappraisal of bilateral adrenalectomy for ACTH-dependent Cushing’s syndrome. Eur J Endocrinol 173(4):M23-32 CAS PubMed Article Google Scholar 6. Nelson DH, Meakin JW, Dealy JB Jr, Matson DD, Emerson K Jr, Thorn GW (1958) ACTH-producing tumor of the pituitary gland. N Engl J Med 259(4):161–164 CAS PubMed Article Google Scholar 7. Guerin C, Taieb D, Treglia G, Brue T, Lacroix A, Sebag F, Castinetti F (2016) Bilateral adrenalectomy in the 21st century: when to use it for hypercortisolism? Endocr Relat Cancer 23(2):R131-142 CAS PubMed Article Google Scholar 8. Katznelson L (2015) Bilateral adrenalectomy for Cushing’s disease. Pituitary 18(2):269–273 CAS PubMed Article Google Scholar 9. Banasiak MJ, Malek AR (2007) Nelson syndrome: comprehensive review of pathophysiology, diagnosis, and management. Neurosurg Focus 23(3):E13 PubMed Article Google Scholar 10. Assie G, Bahurel H, Bertherat J, Kujas M, Legmann P, Bertagna X (2004) The Nelson’s syndrome revisited. Pituitary. 7(4):209–215 PubMed Article Google Scholar 11. Ragnarsson O (2020) Cushing’s syndrome disease monitoring: recurrence, surveillance with biomarkers or imaging studies. Best Pract Res Clin Endocrinol Metab. 34(2):101382 PubMed Article Google Scholar 12. Fountas A, Karavitaki N (2020) Nelson’s syndrome: an update. Endocrinol Metab Clin North Am 49(3):413–432 PubMed Article Google Scholar 13. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097 PubMed PubMed Central Article Google Scholar 14. Wells GA SB, O'Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp 15. Balduzzi S, Rucker G, Schwarzer G (2019) How to perform a meta-analysis with R: a practical tutorial. Evid Based Ment Health 22(4):153–160 PubMed Article Google Scholar 16. Lau J, Ioannidis JP, Schmid CH (1998) Summing up evidence: one answer is not always enough. Lancet 351(9096):123–127 CAS PubMed Article Google Scholar 17. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634 CAS PubMed PubMed Central Article Google Scholar 18. Smith PW, Turza KC, Carter CO, Vance ML, Laws ER, Hanks JB (2009) Bilateral adrenalectomy for refractory Cushing disease: a safe and definitive therapy. J Am Coll Surg 208(6):1059–1064 PubMed Article Google Scholar 19. Mehta GU, Sheehan JP, Vance ML (2013) Effect of stereotactic radiosurgery before bilateral adrenalectomy for Cushing’s disease on the incidence of Nelson’s syndrome. J Neurosurg 119(6):1493–1497 PubMed Article Google Scholar 20. Gil-Cardenas A, Herrera MF, Diaz-Polanco A, Rios JM, Pantoja JP (2007) Nelson's syndrome after bilateral adrenalectomy for Cushing's disease. Surgery. 141(2):147–151 21. Moore TJ, Dluhy RG, Williams GH, Cain JP (1976) Nelson’s syndrome: frequency, prognosis, and effect of prior pituitary irradiation. Ann Intern Med 85(6):731–734 CAS PubMed Article Google Scholar 22. Nabarro JDN (1977) ACTH secreting pituitary tumours. J R Coll Physicians Lond 11(4):363–375 CAS PubMed PubMed Central Google Scholar 23. Scott HW Jr, Liddle GW, Mulherin JL Jr, McKenna TJ, Stroup SL, Rhamy RK (1977) Surgical experience with Cushing’s disease. Ann Surg 185(5):524–534 PubMed PubMed Central Article Google Scholar 24. Cohen KL, Noth RH, Pechinski T (1978) Incidence of pituitary tumors following adrenalectomy. A long-term follow-up study of patients treated for Cushing’s disease. Arch Internal Med 138(4):575–579 CAS Article Google Scholar 25. Jordan RM, Cook DM, Kendall JW, Kerber CW (1979) Nelson’s syndrome and spontaneous pituitary tumor infarction. Arch Intern Med 139(3):340–342 CAS PubMed Article Google Scholar 26. Barnett AH, Livesey JH, Friday K, Donald RA, Espiner EA (1983) Comparison of preoperative and postoperative ACTH concentrations after bilateral adrenalectomy in Cushing’s disease. Clin Endocrinol (Oxf) 18(3):301–305 CAS Article Google Scholar 27. Kasperlik-Zaluska AA, Nielubowicz J, Wislawski J, Hartwig W, Zaluska J, Jeske W, Migdalska B (1983) Nelson’s syndrome: incidence and prognosis. Clin Endocrinol (Oxf) 19(6):693–698 CAS Article Google Scholar 28. Kelly WF, MacFarlane IA, Longson D, Davies D, Sutcliffe H (1983) Cushing’s disease treated by total adrenalectomy: long-term observations of 43 patients. Q J Med 52(206):224–231 CAS PubMed Google Scholar 29. Kuhn JM, Proeschel MF, Seurin DJ, Bertagna XY, Luton JP, Girard FL (1989) Comparative assessment of ACTH and lipotropin plasma levels in the diagnosis and follow-up of patients with Cushing’s syndrome: a study of 210 cases. Am J Med 86(6 Pt 1):678–684 CAS PubMed Article Google Scholar 30. Grabner P, Hauerjensen M, Jervell J, Flatmark A (1991) Long-term results of treatment of cushings-disease by adrenalectomy. Acta Chirurgica- Eur J Surgery 157(8):461–464 CAS Google Scholar 31. McCance DR, Russell CF, Kennedy TL, Hadden DR, Kennedy L, Atkinson AB (1993) Bilateral adrenalectomy: low mortality and morbidity in Cushing’s disease. Clin Endocrinol 39(3):315–321 CAS Article Google Scholar 32. Zeiger MA, Fraker DL, Pass HI, Nieman LK, Cutler GB Jr, Chrousos GP, Norton JA (1993) Effective reversibility of the signs and symptoms of hypercortisolism by bilateral adrenalectomy. Surgery 114(6):1138–1143 CAS PubMed Google Scholar 33. Favia G, Boscaro M, Lumachi F, D’Amico DF (1994) Role of bilateral adrenalectomy in Cushing’s disease. World J Surg 18(4):462–466 CAS PubMed Article Google Scholar 34. Kemink L, Pieters G, Hermus A, Smals A, Kloppenborg P (1994) Patient’s age is a simple predictive factor for the development of Nelson’s syndrome after total adrenalectomy for Cushing’s disease. J Clin Endocrinol Metab 79(3):887–889 CAS PubMed Google Scholar 35. Misra D, Kapur MM, Gupta DK (1994) Incidence of Nelson’s syndrome and residual adrenocortical function in patients of Cushing’s disease after bilateral adrenalectomy. J Assoc Physicians India 42(4):304–305 CAS PubMed Google Scholar 36. Jenkins PJ, Trainer PJ, Plowman PN, Shand WS, Grossman AB, Wass JA, Besser GM (1995) The long-term outcome after adrenalectomy and prophylactic pituitary radiotherapy in adrenocorticotropin-dependent Cushing’s syndrome. J Clin Endocrinol Metab 80(1):165–171 CAS PubMed Google Scholar 37. Pereira MA, Halpern A, Salgado LR, Mendonca BB, Nery M, Liberman B, Streeten DH, Wajchenberg BL (1998) A study of patients with Nelson’s syndrome. Clin Endocrinol (Oxf) 49(4):533–539 CAS Article Google Scholar 38. Imai T, Kikumori T, Funahashi H, Nakao A (2000) Surgical management of Cushing’s syndrome. Biomed Pharmacother 54(1):140–145 Article Google Scholar 39. Nagesser SK, van Seters AP, Kievit J, Hermans J, Krans HM, van de Velde CJ (2000) Long-term results of total adrenalectomy for Cushing’s disease. World J Surg 24(1):108–113 CAS PubMed Article Google Scholar 40. Hofmann BM, Fahlbusch R (2006) Treatment of Cushing’s disease: A retrospective clinical study of the latest 100 cases. Pituitary Surgery - A Modern Approach 34:158–184 Article Google Scholar 41. Thompson SK, Hayman AV, Ludlam WH, Deveney CW, Loriaux DL, Sheppard BC (2007) Improved quality of life after bilateral laparoscopic adrenalectomy for Cushing’s disease: a 10-year experience. Ann Surg 245(5):790–794 PubMed PubMed Central Article Google Scholar 42. Ding XF, Li HZ, Yan WG, Gao Y, Li XQ (2010) Role of adrenalectomy in recurrent Cushing’s disease. Chin Med J 123(13):1658–1662 PubMed Google Scholar 43. Osswald A, Plomer E, Dimopoulou C, Milian M, Blaser R, Ritzel K, Mickisch A, Knerr F, Stanojevic M, Hallfeldt K, Schopohl J, Kuhn KA, Stalla G, Beuschlein F, Reincke M (2014) Favorable long-term outcomes of bilateral adrenalectomy in Cushing’s disease. Eur J Endocrinol 171(2):209–215 CAS PubMed Article Google Scholar 44. Prajapati OP, Verma AK, Mishra A, Agarwal G, Agarwal A, Mishra SK (2015) Bilateral adrenalectomy for Cushing’s syndrome: pros and cons. Indian J Endocrinol Metabol 19(6):834–840 CAS Article Google Scholar 45. Espinosa-de-Los-Monteros AL, Sosa-Eroza E, Espinosa E, Mendoza V, Arreola R, Mercado M (2017) Long-term outcome of the different treatment alternatives for recurrent and persistent cushing disease. Endocrine Pract: Off J Am College Endocrinol Am Assoc Clin Endocrinol 23(7):759–767 Article Google Scholar 46. Graffeo CS, Perry A, Carlstrom LP, Meyer FB, Atkinson JLD, Erickson D, Nippoldt TB, Young WF, Pollock BE, Van Gompel JJ (2017) Characterizing and predicting the Nelson-Salassa syndrome. J Neurosurg 127(6):1277–1287 CAS PubMed Article Google Scholar 47. Nankova A, Yaneva M, Elenkova A, Tcharaktchiev D, Marinov M, Hadzhiyanev A, Sechanov T, Gantchev G, Todorov G, Kirilov G, Kalinov K, Andreeva M, Zacharieva S (2018) Cushing’s syndrome: a historic review of the treatment strategies and corresponding outcomes in a single tertiary center over the past half-century. Hormone Metab Res 50(4):280–289 CAS Article Google Scholar 48. Chiloiro S, Giampietro A, Raffaelli M, D’Amato G, Bima C, Lauretti L, Anile C, Lombardi CP, Rindi G, Bellantone R, De Marinis L, Pontecorvi A, Bianchi A (2019) Synchronous bilateral adrenalectomy in ACTH-dependent hypercortisolism: predictors, biomarkers and outcomes. Endocrine 66(3):642–649 CAS PubMed Article Google Scholar 49. Cohen AC, Goldney DC, Danilowicz K, Manavela M, Rossi MA, Gomez RM, Cross GE, Bruno OD (2019) Long-term outcome after bilateral adrenalectomy in Cushing’s disease with focus on Nelson’s syndrome. Arch Endocrinol Metab 63(5):470–477 50. Nagendra L, Bhavani N, Pavithran PV, Kumar GP, Menon UV, Menon AS, Kumar L, Kumar H, Nair V, Abraham N, Narayanan P (2019) Outcomes of bilateral adrenalectomy in Cushing’s syndrome. Indian J Endocrinol Metab 23(2):193–197 PubMed PubMed Central Article Google Scholar 51. Sarkis P, Rabilloud M, Lifante JC, Siamand A, Jouanneau E, Gay E, Chaffanjon P, Chabre O, Raverot G (2019) Bilateral adrenalectomy in Cushing’s disease: altered long-term quality of life compared to other treatment options. Ann Endocrinol 80(1):32–37 Article Google Scholar 52. Assie G, Bahurel H, Coste J, Silvera S, Kujas M, Dugue MA, Karray F, Dousset B, Bertherat J, Legmann P, Bertagna X (2007) Corticotroph tumor progression after adrenalectomy in Cushing’s disease: a reappraisal of Nelson’s Syndrome. J Clin Endocrinol Metab 92(1):172–179 CAS PubMed Article Google Scholar 53. Das L, Bhansali A, Pivonello R, Dutta P, Bhadada SK, Ahuja CK, Mavuduru R, Kumar S, Behera A, Saikia UN, Dhandapani S, Walia R (2020) ACTH increment post total bilateral adrenalectomy for Cushing’s disease: a consistent biosignature for predicting Nelson’s syndrome. Pituitary 23(5):488–497 CAS PubMed Article Google Scholar 54. Barber TM, Adams E, Ansorge O, Byrne JV, Karavitaki N, Wass JA (2010) Nelson’s syndrome. Eur J Endocrinol 163(4):495–507 CAS PubMed Article Google Scholar 55. Reincke M, Albani A, Assie G, Bancos I, Brue T, Buchfelder M, Chabre O, Ceccato F, Daniele A, Detomas M, Di Dalmazi G, Elenkova A, Findling J, Grossman AB, Gomez-Sanchez CE, Heaney AP, Honegger J, Karavitaki N, Lacroix A, Laws ER, Losa M, Murakami M, Newell-Price J, Pecori Giraldi F, Perez-Rivas LG, Pivonello R, Rainey WE, Sbiera S, Schopohl J, Stratakis CA, Theodoropoulou M, van Rossum EFC, Valassi E, Zacharieva S, Rubinstein G, Ritzel K (2021) Corticotroph tumor progression after bilateral adrenalectomy (Nelson’s syndrome): systematic review and expert consensus recommendations. Eur J Endocrinol. https://doi.org/10.1530/EJE-20-1088 56. Patel J, Eloy JA, Liu JK (2015) Nelson’s syndrome: a review of the clinical manifestations, pathophysiology, and treatment strategies. Neurosurg Focus 38(2):E14 PubMed Article Google Scholar 57. Fountas A, Lim ES, Drake WM, Powlson AS, Gurnell M, Martin NM, Seejore K, Murray RD, MacFarlane J, Ahluwalia R, Swords F, Ashraf M, Pal A, Chong Z, Freel M, Balafshan T, Purewal TS, Speak RG, Newell-Price J, Higham CE, Hussein Z, Baldeweg SE, Dales J, Reddy N, Levy MJ, Karavitaki N (2020) Outcomes of patients with Nelson's syndrome after primary treatment: a multicenter study from 13 UK pituitary centers. J Clin Endocrinol Metab 105(5):1527–1537 Download references Acknowledgements We would like to thank Therese Svanberg, librarian at the Medical Library at Sahlgrenska University Hospital for her expert assistance with the literature search. Funding Open access funding provided by University of Gothenburg. The study was financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-593301) and a grant from the Gothenburg Society of Medicine. Author information Affiliations Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, 413 45, Gothenburg, Sweden Eleni Papakokkinou, Marta Piasecka, Dimitrios Chantzichristos, Daniel S. Olsson, Gudmundur Johannsson & Oskar Ragnarsson The Department of Endocrinology, Sahlgrenska University Hospital, Blå stråket 5, 413 45, Gothenburg, Sweden Eleni Papakokkinou, Marta Piasecka, Dimitrios Chantzichristos, Daniel S. Olsson, Gudmundur Johannsson & Oskar Ragnarsson Department of Environmental and Occupational Health School of Public Health and Community Medicine, University of Gothenburg, 4053, Gothenburg, Sweden Hanne Krage Carlsen Department of Public Health and Clinical Medicine, Umeå University, 901 87, Umeå, Sweden Per Dahlqvist Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176, Stockholm, Sweden Maria Petersson, Katarina Berinder, Sophie Bensing, Charlotte Höybye & Henrik Falhammar Department of Endocrinology, Karolinska University Hospital, 171 76, Stockholm, Sweden Maria Petersson, Katarina Berinder, Sophie Bensing, Charlotte Höybye & Henrik Falhammar Department of Endocrinology and Diabetes, Uppsala University Hospital, and Department of Medical Sciences, Endocrinology and Mineral Metabolism, Uppsala University, 751 85, Uppsala, Sweden Britt Edén Engström Department of Endocrinology, Skåne University Hospital, University of Lund, 205 02, Malmö, Sweden Pia Burman Department of Endocrinology, Skåne University Hospital, 222 42, Lund, Sweden Cecilia Follin, David Petranek & Eva Marie Erfurth Department of Endocrinology and Department of Medical and Health Sciences, Linköping University, 581 83, Linköping, Sweden Jeanette Wahlberg & Bertil Ekman Department of Internal Medicine, School of Health and Medical Sciences, Örebro University, 702 81, Örebro, SE, Sweden Jeanette Wahlberg, Anna-Karin Åkerman & Erik Schwarcz Corresponding author Correspondence to Oskar Ragnarsson. Ethics declarations Conflict of interest The authors have nothing to disclose. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information Below is the link to the electronic supplementary material. Supplementary file1 (DOCX 1208 kb) Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Reprints and Permissions About this article Cite this article Papakokkinou, E., Piasecka, M., Carlsen, H.K. et al. Prevalence of Nelson’s syndrome after bilateral adrenalectomy in patients with cushing’s disease: a systematic review and meta-analysis. Pituitary (2021). https://doi.org/10.1007/s11102-021-01158-z Download citation Accepted18 May 2021 Published25 May 2021 DOIhttps://doi.org/10.1007/s11102-021-01158-z Share this article Anyone you share the following link with will be able to read this content: Get shareable link Provided by the Springer Nature SharedIt content-sharing initiative Keywords Bilateral adrenalectomy Cushing’s disease Corticotroph adenoma Nelson’s syndrome From https://link.springer.com/article/10.1007/s11102-021-01158-z
  2. Sethi A, et al. Clin Endocrinol. 2019;doi:10.1111/CEN.14146. January 5, 2020 Obesity is common at diagnosis of pituitary adenoma in childhood and may persist despite successful treatment, according to findings published in Clinical Endocrinology. “The importance of childhood and adolescent obesity on noncommunicable disease in adult life is well recognized, and in this new cohort of patients, we report that obesity is common at presentation of pituitary adenoma in childhood and that successful treatment is not necessarily associated with weight loss,” Aashish Sethi, MD, MBBS, a pediatric endocrinologist in the department of endocrinology at Alder Hey Children’s Hospital in Liverpool, United Kingdom, and colleagues wrote. “We have reported obesity, and obesity-related morbidity in a mixed cohort of children and young adults previously, but [to] our knowledge, this is the first time this observation has been reported in a purely pediatric cohort.” In a retrospective study, Sethi and colleagues analyzed clinical and radiological data from 24 white children from Alder Hey Children’s Hospital followed for a median of 3.3 years between 2000 and 2019 (17 girls; mean age at diagnosis, 15 years). Researchers assessed treatment modality (medical, surgical or radiation therapy), pituitary hormone deficiencies and BMI, as well as results of any genetic testing. Within the cohort, 13 girls had prolactinomas (mean age, 15 years), including 10 macroadenomas between 11 mm and 35 mm in size. Children presented with menstrual disorders (91%), headache (46%), galactorrhea (46%) and obesity (38%). Nine children were treated with cabergoline alone, three also required surgery, and two were treated with the dopamine agonist cabergoline, surgery and radiotherapy. Five children had Cushing’s disease (mean age, 14 years; two girls), including one macroadenoma. Those with Cushing’s disease presented with obesity (100%), short stature (60%) and headache (40%). Transsphenoidal resection resulted in biochemical cure; however, two patients experienced relapse 3 and 6 years after surgery, respectively, requiring radiotherapy. One patient also required bilateral adrenalectomy. Six children had a nonfunctioning pituitary adenoma (mean age, 16 years; two girls), including two macroadenomas. These children presented with obesity (67%), visual field defects (50%) and headache (50%). Four required surgical resections, with two experiencing disease recurrence after surgery and requiring radiotherapy. During the most recent follow-up exam, 13 children (54.1%) had obesity, including 11 who had obesity at diagnosis. “The persistence of obesity following successful treatment, in patients with normal pituitary function, suggests that mechanisms other than pituitary hormone excess or deficiency may be important,” the researchers wrote. “It further signifies that obesity should be a part of active management in cases of pituitary adenoma from diagnosis.” – by Regina Schaffer Disclosures: The authors report no relevant financial disclosures. From https://www.healio.com/endocrinology/adrenal/news/online/%7Bde3fd83b-e8e0-4bea-a6c2-99eb896356ab%7D/long-term-obesity-persists-despite-pituitary-adenoma-treatment-in-childhood
  3. Approximately 20% of a cohort of adults with Cushing’s syndrome experienced at least one thrombotic event after undergoing pituitary or adrenal surgery, with the highest risk observed for those undergoing bilateral adrenalectomy, according to findings from a retrospective analysis published in the Journal of the Endocrine Society. “We have previously showed in a recent meta-analysis that Cushing’s syndrome is associated with significantly increased venous thromboembolic events odds vs. the general population, though the risk is lower than in patients undergoing major orthopedic surgery,” Maria Fleseriu, MD, FACE, professor of neurological surgery and professor of medicine in the division of endocrinology, diabetes and clinical nutrition in the School of Medicine at Oregon Health & Science University and director of the OHSU Northwest Pituitary Center, told Healio. “However, patients undergoing many types of orthopedic surgeries have scheduled thromboprophylaxis, especially postsurgery, which is not the standard of care in patients with Cushing’s syndrome. In this study, we wanted to look in more detail at the rates of all thrombotic events, both arterial and venous, in patients at our specialized pituitary center over more than a decade.” In a retrospective, longitudinal study, Fleseriu and colleagues analyzed data from 208 individuals with Cushing’s syndrome undergoing surgical (pituitary, unilateral and bilateral adrenalectomy) and medical treatment at a single center (79.3% women; mean age at presentation, 45 years; mean BMI, 33.9 kg/m²; 41.8% with diabetes). Individuals with severe illness and immediate mortality were excluded. Thromboembolic events (myocardial infarction, deep venous thrombosis [DVT], and pulmonary embolism or stroke) were recorded at any point up until last patient follow-up. Researchers assessed all patients who received anticoagulation in the immediate postoperative period and up to 3 months after surgery, recording doses and complications for anticoagulation. Within the cohort, 39 patients (18.2%) experienced at least one thromboembolic event (56 total events; 52% venous), such as extremity DVT (32%), cerebrovascular accident (27%), MI (21%), and pulmonary embolism (14%). Of those who experienced a thromboembolic event, 40.5% occurred within 60 days of surgery. Researchers found that 14 of 36 patients who underwent bilateral adrenalectomy experienced a thromboembolic event, for an OR of 3.74 (95% CI, 1.69-8.27). Baseline 24-hour urinary free cortisol levels did not differ for patients with or without thromboembolic event after bilateral adrenalectomy. “Despite following these patients over time, results almost surprised us,” said Fleseriu, also an Endocrine Today Editorial Board Member. “The risk of thromboembolic events in patients with Cushing’s syndrome was higher than we expected, approximately 20%. Many patients had more than one event, with higher risk at 30 to 60 days postoperatively. Use of a peripherally inserted central catheter line clearly increased risk of upper extremity DVT.” Among 197 patients who underwent surgery, 50 (25.38%) received anticoagulation after surgery with 2% experiencing bleeding complications. “We clearly need to understand more about what happens in patients with Cushing’s syndrome for all comorbidities, but especially thrombosis, and find the factors that predict higher risk and use anticoagulation in those patients,” Fleseriu said. “We have shown that among patients who had anticoagulation, risks were minimal. We also have to think more about timelines for these thromboembolic events and the duration of anticoagulation, and probably to expand it up to 30 to 60 days postoperatively if there are no contraindications, especially for patients undergoing bilateral adrenalectomy.” Fleseriu cautioned that the findings do not necessarily suggest that every individual with Cushing’s syndrome needs anticoagulation therapy, as the study was retrospective. Additionally, sex, age, BMI, smoking status, estrogen or testosterone supplementation, diabetes and hypertension — all known factors for increased thrombosis risk among the general population — were not found to significantly increase the risk for developing a thromboembolic event, Fleseriu said. “As significantly more patients have exogenous Cushing’s syndrome than endogenous Cushing’s syndrome and many of these patients undergo surgeries, we hope that our study increased awareness regarding thromboembolic risks and the need to balance advantages of thromboprophylaxis with risk of bleeding,” Fleseriu said. – by Regina Schaffer For more information: Maria Fleseriu, MD, FACE, can be reached at fleseriu@ohsu.edu. Disclosure: Fleseriu reports she has received research funding paid to her institution from Novartis and Strongbridge and has received consultant fees from Novartis and Strongbridge. From https://www.healio.com/endocrinology/neuroendocrinology/news/online/%7Bce267e5a-0d32-4171-abc8-34369b455fcf%7D/risk-for-thrombotic-events-high-after-cushings-syndrome-surgery
  4. Bilateral adrenalectomy, in which the adrenal glands are removed, has a bigger negative impact on the quality of life of patients with Cushing’s disease than other treatment options, a recent study suggests. This may be due to the longer exposure to high levels of cortisol in these patients, which is known to greatly affect their quality of life, the authors hypothesize. The study, “Bilateral adrenalectomy in Cushing’s disease: Altered long-term quality of life compared to other treatment options,” was published in the journal Annales d’Endocrinologie. Cushing’s disease is caused by a tumor in the pituitary gland in the brain that secretes large amounts of adrenocorticotropic hormone, which, in turn, stimulates the adrenal glands to produce high levels of cortisol (a glucocorticoid hormone). The gold standard for treating Cushing’s disease is the surgical removal of the pituitary gland tumor. However, 31% of these patients still require a second-line treatment — such as another surgery, radiotherapy, medical treatment, and/or bilateral adrenalectomy — due to persistent or recurrent disease. Bilateral adrenalectomy is increasingly used to treat patients with Cushing’s disease, with high rates of success and low mortality rates. However, since the absence of adrenal glands leads to a sharp drop in cortisol, this treatment implies lifelong glucocorticoid replacement therapy and increases the risk of developing Nelson syndrome. Nelson syndrome is characterized by the enlargement of the pituitary gland and the development of pituitary gland tumors, and is estimated to occur in 15-25% of Cushing’s patients who have a bilateral adrenalectomy. Despite being cured with any of these treatment options, patients still seem to have a lower quality of life than healthy people. In addition, there is limited data on the impact of several of the treatment options on quality of life. Researchers in France evaluated the long-term quality of life of Cushing’s disease patients who underwent bilateral adrenalectomy and compared it with other therapeutic options. Quality of life was assessed through three questionnaires: one of general nature, the Short Form-36 Health Survey (SF-36); one on disease-specific symptoms, the Cushing QoL questionnaire; and the last focused on mental aspects, the Beck depression inventory (BDI). Researchers analyzed the medical data, as well as the results of the questionnaires, of 34 patients with Cushing’s disease — 24 women and 10 men — at two French centers. The patients’ mean age was 49.3, and 17 had undergone bilateral adrenalectomy, while the remaining 17 had surgery, radiotherapy, or medical treatment. Results showed that patients who underwent a bilateral adrenalectomy were exposed to high levels of cortisol significantly longer (6.1 years) than those on other treatment options (1.3 years). This corresponds with the fact that this surgery is conducted only in patients with severe disease that was not controlled with first-line and/or second-line treatment. These patients also showed a lower quality of life — particularly in regards to the general health, bodily pain, vitality, and social functioning aspects of the SF-36 questionnaire, and the Cushing QoL questionnaire and BDI — compared with those who underwent other therapeutic options. This and other studies support the hypothesis that these patients’ lower quality of life may be caused by longer exposure to high cortisol levels, and “its physical and psychological consequences, as well as the repeated treatment failures,” according to the researchers. Additionally, the presence of Nelson syndrome in these patients was associated with a significantly lower quality of life related to mental aspects. The team also found that adrenal gland insufficiency was a major predictor of a lower quality of life in these patients, regardless of the therapeutic option, suggesting it may have a stronger negative impact than the type of treatment. They noted, however, that additional and larger prospective studies are necessary to confirm these results. From https://cushingsdiseasenews.com/2018/09/28/bilateral-adrenalectomy-lowers-cushing-patients-quality-life-study/
  5. MaryO Note: Natalie had a BLA in March, 2008. She died April 21, 2008. In Memoriam Natalie Fay Monday, April 21, 2008 2001 Cushing's Lunch. From left: Joe (Natalie's husband), Natalie and Linda Natalie Fay (Natalie65), died April 21, 2008. She was only 42 and had recently had a BLA. I first met Natalie at a local lunch in November of 2001 and have seen her seval times since then. Natalie started the original "Dammit Dolls" that circulated around the country until people refused to pass them along anymore. Dammit Doll. Natalie also made counted cross-stitch Cushing's Awareness Pins: Natalie's bio... http://www.cushings-help.com/natalies_story.htm Some recent past posts. February 10, 2008 going to UVA I am going for my first visit with Dr. Hanks at UVA on the 20th. I will also see Dr. Vance that day. I haven't seen her before either. I am planning on having bilateral adrenal surgery in March. I am a little nervous about this, but it is going to be a positive thing I hope. I would love to hear from anyone who has had this done so that I will have an idea of what to expect. after surgery. Thanks! Natalie March 18, 2008 surgery update Hey everyone! I'm back! It has been a very slow week and I'm just satrting to feel like moving around again. I had BLA on the 10th and came home on friday. My parents have taken my boys (3 & 6) home to Va. I have missed them so much this week, but I think it was the right thing to do. I don't know how I would have done it without them. I am still very sore and tired at times, but I'm coming along. Sorry this has taken so long to get out to you guys, I thought things were taken care of but I was wrong. Oh Well! I'm doing good and I'll keep in touch. Thanks for all of your thoughts and prayers. Natalie Message Board Signature: pit surgery 1990 traditional 30 days radiation 1990 pit surgery 1995 sterotactic radiation surgery 1995 2004 still have remaining tumor cortisol levels still off balance BLA March 10, 2008 Tributes and Memories on the message boards... Our first local DC area Cushie lunch November 17, 2001 with Linda, Jayne, me and Natalie - all in Cushe Colors [Photographer: Robin] Our first local DC area Cushie lunch November 17, 2001 with Jayne, Linda, Natalie, MaryO and Dianne [Photographer: Robin] Our first local DC area Cushie lunch November 17, 2001 with Jayne, Linda, Natalie, MaryO and Dianne [Photographer: TomO] Our second local DC area Cushie lunch February 9, 2002 all the families [Photographer: Robin] Our second local DC area Cushie lunch February 9, 2002 with Jayne, Marcia, Heather, Natalie and MaryO [Photographer: Robin] Our second local DC area Cushie lunch February 9, 2002 with Jayne, Marcia, Heather, Natalie and MaryO [Photographer: Robin] Our second local DC area Cushie lunch February 9, 2002 with Jayne, Marcia, Heather, Natalie and MaryO. LynneInVa made the roses for us from candles. [Photographer: Robin] Our next local DC area Cushie lunch May 4, 2002 with lots of us! [Photographer: Robin] Our next local DC area Cushie lunch May 4, 2002 with lots of us! [Photographer: Robin] Our next local DC area Cushie lunch May 4, 2002 with lots of us! [Photographer: Robin] Our next local DC area Cushie lunch May 4, 2002 with lots of us! [Photographer: Robin] Our next local DC area Cushie lunch May 4, 2002 with Pat, MaryO, Ruth, Natalie, Susan, Jayne [Photographer: TomO] Our next local DC area Cushie lunch May 4, 2002 with Pat, MaryO, Ruth, Natalie, Susan, Jayne [Photographer: Robin] Our next local DC area Cushie lunch May 4, 2002 with Joe, Jed and Catherine [Photographer: Robin] Our three families: Tom and MaryO, Natalie and Joe, Robin and Jayne...and kids [Photographer: a waitress] Our three families: Tom and MaryO, Natalie and Joe, Robin and Jayne...and kids [Photographer: a waitress] TomO being silly, stealing Catherine's nose. [Photographer: Robin] http://www.wrightfuneralhome.org/index.cfm Natalie Grissom Fay (June 11, 1965 - April 21, 2008) Guest Book | Sign Guest Book Courtland, Virginia– Natalie Grissom Fay, 42, passed away April 21, 2008 at St. Mary’s Hospital in Leonardtown, Md. She was born in Petersburg, Va, a daughter of Edward Scott and Nan Lucy Grissom and was a 1983 graduate of Southampton High School. Natalie actively supported several Cushing Support Groups, and was a member of the Patuxent Presbyterian Church. Surviving in addition to her parents is her husband, Joseph P. Fay; two sons, Joseph Edward (Jed) Fay and Nathan Lee Fay all of Hollywood, Md.; one sister, Annette G. Stephenson of Courtland, Va.; two nephews, Scott and Vance Stephenson; and her father-in-law, Edward K. Fay and wife, Sunee, of Deltona, Fl. The funeral will be conducted at 2 pm Friday at Wright Funeral Home with the Rev. Edmund Ellis officiating. Burial will follow in Riverside Cemetery. The family will receive friends from 7 to 9 pm Thursday at the home of Edward and Nan Grissom, 16046 Wakefield Road, Courtland, and suggest that in lieu of flowers, memorials may be made to Cushings Help, c/o Mary O’Connor.
  6. Katrin Ritzel, Felix Beuschlein, Anne Mickisch, Andrea Osswald, Harald J. Schneider, Jochen Schopohl and Martin Reincke -Author Affiliations Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, D-80336 München, Germany Address all correspondence and requests for reprints to: Martin Reincke, M.D., Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 München, Germany. E-mail:Martin.Reincke@med.uni-muenchen.de. AbstractBackground: The outcome of bilateral adrenalectomy (BADx) in patients with Cushing’s syndrome (CS) is not well characterized. Methods: A literature search was performed with the search terms “bilateral adrenalectomy” or “total adrenalectomy” and “Cushing’s” or “Cushing.” Immediate and long-term outcomes after BADx in CS were analyzed using descriptive statistics (median [range]). Results: From 549 screened publications, 37 studies met inclusion criteria (1320 patients, 82% having Cushing’s disease [CD], 13% having ectopic CS, and 5% having primary adrenal hyperplasia). Surgical morbidity and mortality of BADx (23 studies, 739 patients) were 18% (6–31) and 3% (0–15), respectively. In patients with CD, surgical mortality was below 1%. Although residual cortisol secretion due to accessory adrenal tissue or adrenal remnants was found in 3–34% (5 studies, 236 patients), less than 2% had a relapse of CS. Symptoms of hypercortisolism (eg, hypertension, obesity, or depression) improved in the majority of the patients after BADx (7 studies, 195 patients). The number of adrenal crises per 100 patient-years was 9.3 (6 studies, 203 patients). Nelson’s syndrome occurred in 21% (0–47) of the patients (24 studies, 768 patients). Mortality (23 studies, 690 patients) was 17% (0–88) at a follow-up of 41 months (14–294). Remarkably, 46% of the patients died in the first year after surgery. The median ages at death were 62 years (CD) and 53 years (ectopic CS). Conclusion: BADx is relatively safe and provides adequate success. Excess mortality within the first year after surgery suggests that intensive clinical care for patients after BADx is warranted. FootnotesFor editorial see page 3974 Abbreviations: BADx bilateral adrenalectomy BAH bilateral adrenal hypercortisolism CD Cushing’s disease CS Cushing’s syndrome ECS ectopic CS NS Nelson’s syndrome QOL quality of life TSS transsphenoidal surgery. Copyright © 2013 by The Endocrine SocietyFrom http://jcem.endojournals.org/content/98/10/3939.abstract
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