Characterizing and predicting the Nelson-Salassa syndrome

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  • 1 Department of Neurologic Surgery, and
  • | 2 Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota
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OBJECTIVE

Nelson-Salassa syndrome (NSS) is a rare consequence of bilateral adrenalectomy (ADX) for refractory hypercortisolism due to Cushing disease (CD). Although classically defined by rapid growth of a large, invasive, adrenocorticotropin hormone (ACTH)–secreting pituitary tumor after bilateral ADX that causes cutaneous hyperpigmentation, visual disturbance, and high levels of ACTH, clinical experience suggests more variability.

METHODS

The authors conducted a retrospective chart review of all patients 18 years and older with a history of bilateral ADX for CD, adequate pituitary MRI, and at least 2 years of clinical follow-up. Statistical tests included Student's t-test, chi-square test, Fisher's exact test, multivariate analysis, and derived receiver operating characteristic curves.

RESULTS

Between 1956 and 2015, 302 patients underwent bilateral ADX for the treatment of hypercortisolism caused by CD; 88 had requisite imaging and follow-up (mean 16 years). Forty-seven patients (53%) had radiographic progression of pituitary disease and were diagnosed with NSS. Compared with patients who did not experience progression, those who developed NSS were significantly younger at the time of CD diagnosis (33 vs 44 years, p = 0.007) and at the time of bilateral ADX (35 vs 49 years, p = 0.007), had larger tumors at the time of CD diagnosis (6 mm vs 1 mm, p = 0.03), and were more likely to have undergone external-beam radiation therapy (EBRT, 43% vs 12%, p = 0.005). Among NSS patients, the mean tumor growth was 7 mm/yr (SE 6 mm/yr); the median tumor growth was 3 mm/yr. Prevalence of pathognomonic symptoms was low; the classic triad occurred in 9%, while hyperpigmentation without visual field deficit was observed in 23%, and 68% remained asymptomatic despite radiographic disease progression. NSS required treatment in 14 patients (30%).

CONCLUSIONS

NSS is a prevalent sequela of CD after bilateral ADX and affects more than 50% of patients. However, although radiological evidence of NSS is common, it is most often clinically indolent, with only a small minority of patients developing the more aggressive disease phenotype characterized by clinically meaningful symptoms and indications for treatment. Young age at the time of CD diagnosis or treatment with bilateral ADX, large tumor size at CD diagnosis, and EBRT are associated with progression to NSS and may be markers of aggressiveness.

ABBREVIATIONS

ACTH = adrenocorticotropin hormone; ADX = adrenalectomy; CD = Cushing disease; EBRT = external-beam radiation therapy; NSS = Nelson-Salassa syndrome; SRS = stereotactic radiosurgery; TSS = transsphenoidal surgery.

OBJECTIVE

Nelson-Salassa syndrome (NSS) is a rare consequence of bilateral adrenalectomy (ADX) for refractory hypercortisolism due to Cushing disease (CD). Although classically defined by rapid growth of a large, invasive, adrenocorticotropin hormone (ACTH)–secreting pituitary tumor after bilateral ADX that causes cutaneous hyperpigmentation, visual disturbance, and high levels of ACTH, clinical experience suggests more variability.

METHODS

The authors conducted a retrospective chart review of all patients 18 years and older with a history of bilateral ADX for CD, adequate pituitary MRI, and at least 2 years of clinical follow-up. Statistical tests included Student's t-test, chi-square test, Fisher's exact test, multivariate analysis, and derived receiver operating characteristic curves.

RESULTS

Between 1956 and 2015, 302 patients underwent bilateral ADX for the treatment of hypercortisolism caused by CD; 88 had requisite imaging and follow-up (mean 16 years). Forty-seven patients (53%) had radiographic progression of pituitary disease and were diagnosed with NSS. Compared with patients who did not experience progression, those who developed NSS were significantly younger at the time of CD diagnosis (33 vs 44 years, p = 0.007) and at the time of bilateral ADX (35 vs 49 years, p = 0.007), had larger tumors at the time of CD diagnosis (6 mm vs 1 mm, p = 0.03), and were more likely to have undergone external-beam radiation therapy (EBRT, 43% vs 12%, p = 0.005). Among NSS patients, the mean tumor growth was 7 mm/yr (SE 6 mm/yr); the median tumor growth was 3 mm/yr. Prevalence of pathognomonic symptoms was low; the classic triad occurred in 9%, while hyperpigmentation without visual field deficit was observed in 23%, and 68% remained asymptomatic despite radiographic disease progression. NSS required treatment in 14 patients (30%).

CONCLUSIONS

NSS is a prevalent sequela of CD after bilateral ADX and affects more than 50% of patients. However, although radiological evidence of NSS is common, it is most often clinically indolent, with only a small minority of patients developing the more aggressive disease phenotype characterized by clinically meaningful symptoms and indications for treatment. Young age at the time of CD diagnosis or treatment with bilateral ADX, large tumor size at CD diagnosis, and EBRT are associated with progression to NSS and may be markers of aggressiveness.

ABBREVIATIONS

ACTH = adrenocorticotropin hormone; ADX = adrenalectomy; CD = Cushing disease; EBRT = external-beam radiation therapy; NSS = Nelson-Salassa syndrome; SRS = stereotactic radiosurgery; TSS = transsphenoidal surgery.

The Nelson-Salassa syndrome (NSS) is a rare and severe neuroendocrine sequela of bilateral adrenalectomy (ADX), a procedure performed to treat symptomatic hypercortisolism in the setting of refractory Cushing disease (CD). Originally reported as a single case by Nelson and colleagues in 1958,34 and subsequently in a series of 5 patients reported on by Salassa and colleagues in 1959,41 the syndrome is classically associated with a rapidly growing, adrenocorticotropin hormone (ACTH)–secreting pituitary adenoma causing visual field deficit and ACTH-driven cutaneous hyperpigmentation.3,10

Although more than 100 cases of NSS have been documented in reports or short series, definitive diagnostic criteria have not been clearly established, and a cursory review of the literature suggests that the pathognomonic clinical triad is frequently incomplete or absent altogether.36 Furthermore, an optimal treatment paradigm has not yet been established, and our understanding of the disease is continuously evolving, with previous authors advocating transsphenoidal surgery (TSS), external-beam radiation therapy (EBRT), stereotactic radiosurgery (SRS), or medical therapy—alone and in various combinations.1,36

With this striking variability in presentation and management in mind, the goal of this study was to analyze the clinical and radiographic features of NSS in a large, single-institution series of CD patients who underwent bilateral ADX, to better define diagnostic criteria and identify predictive factors that may better inform treatment strategies for what is broadly considered a rare but feared treatment sequela in refractory CD.

Methods

Patient Search and Inclusion Criteria

The study cohort was compiled by searching institutional operative reports and surgical databases for patients who had bilateral ADX between 1956 and 2015, as well as institutional pathology reports by diagnosis and site codes. Patients without at least 2 years of radiographic follow-up, or individuals younger than 18 years of age at time of bilateral ADX, were excluded. Patients with both pre- and postbilateral ADX pituitary MRI were included; in patients for whom serial postbilateral ADX imaging was available without preoperative MRI for comparison, radiographs were considered sufficient to diagnose or exclude NSS and therefore merit study inclusion if at least 2 sequential scans were available, and either the first postbilateral ADX study demonstrated gross-total resection, or the first 2 postoperative scans demonstrated stable residual tumor, which was also documented in the medical record to have existed prior to bilateral adrenalectomy. Excluded patients were secondarily reviewed for date and cause of death.

Radiographic Review

Charts for the patients meeting the aforementioned criteria were reviewed for comprehensive demographic, clinical, laboratory, radiographic, treatment, and pathological information. NSS was defined using radiographic criteria; diagnosis required at least 2 mm of tumor growth in 1 dimension after bilateral ADX in comparison with preceding MRI studies. As our institutional protocols for pituitary imaging specify 1- to 2-mm-thick slices, this was considered the minimum detectable difference in tumor size that would not be confounded by technical differences between studies. Images were reviewed and measured using standardized software measurement tools by study staff in a blinded fashion and compared with the original radiology findings; instances of disagreement were resolved by blinded review performed by a second, senior study staff member. Laboratory studies, including serum cortisol and ACTH concentrations, were reviewed at the time of CD diagnosis, prior to bilateral ADX, and at NSS diagnosis.

Clinical End Points and Statistical Analysis

Where possible, a comprehensive treatment history was documented for each study patient, including timing and indication for neurosurgical, radiotherapeutic/radiosurgical, and medical interventions both prior to and following NSS diagnosis. Other end points captured included clinical complications of CD (myopathy, cushingoid skin changes, visual field deficit, apoplexy, nonsurgical diabetes insipidus, and cataracts), medical comorbidities (stroke, myocardial infarction, hypertension, osteoporosis, depression/anxiety/psychosis, obesity, and Type 2 diabetes/metabolic syndrome), and neurosurgical complications (postoperative diabetes insipidus, panhypopituitarism, early and delayed CSF leak, postoperative visual field deficit, hemorrhage, wound infection, and meningitis). All-cause and pituitary-specific mortality data were also recorded. Pathology reports were reviewed for abnormal immunohistochemical staining of pituitary hormones, chromogranin, mutated p53, alpha subunit glycoprotein, or CAM-5.2, as well as other abnormal findings, including Crooke's hyaline change, diffuse cytokeratin expression, or periodic acid–Schiff positivity.

Patients meeting study criteria for diagnosis of NSS were compared with those who did not; statistical tests included Student's t-test, chi-square test, Fisher's exact test, multivariate analysis, and derived receiver operating characteristic curves. All statistical testing was completed using JMP (version 10.0.0, SAS Institute Inc.).

Results

Patient Demographics and Presenting History

A preliminary search revealed 302 patients who underwent bilateral ADX for CD within the study period, of whom 88 had requisite pituitary MRI studies available for review (dating 1996–2015), as well as the requisite 2 years of minimum radiographic follow-up. Based on study criteria, 47 of these patients were diagnosed with NSS; clinical, laboratory, radiographic, treatment, and pathological findings in these patients were reviewed in detail and compared with the 41 patients who did not experience progression after bilateral ADX.

Three-quarters of the patients in both groups were female; however, patients who went on to develop NSS were significantly younger—both at CD diagnosis and bilateral ADX (33 years vs 44 years, p = 0.007, and 35 years vs 49 years, p = 0.007, respectively; Table 1). The mean time from CD diagnosis to TSS was comparable at less than 1 year; however, NSS patients underwent bilateral ADX significantly earlier (3 years vs 5 years, p = 0.05; Table 1). Patients who went on to develop NSS presented with significantly larger adenomas on imaging at the time of CD diagnosis (6 mm vs 1 mm, p = 0.03). Macroadenoma, defined as a tumor larger than 10 mm in maximal diameter, was only observed in patients who progressed to NSS (6% vs 0%, p = 0.2; Table 1). Approximately one-quarter of all patients in both groups underwent more than 1 TSS; however, EBRT for treatment of either persistent CD or tumor recurrence administered prior to bilateral ADX was 3 times more common among patients who progressed to NSS (43% vs 12%, p = 0.005; Table 1). Indications for bilateral ADX were inconsistently documented; however, where available for review, they were broadly similar (Table 1).

TABLE 1.

Patient demographics and presenting history

VariableNSS (n = 47)Non-NSS (n = 41)p Value
Female sex34 (72)30 (70)0.9
CD clinical history
  Mean age at CD diagnosis, yrs33 ± 2 (17–63)44 ± 3 (18–75)0.007
  Mean age at bilat ADX, yrs35 ± 2 (25–68)49 ± 2 (18–78)0.007
  Mean yrs btwn CD & TSS<1 ± 1 (0–2)<1 ± 1 (0–2)0.9
  Mean yrs btwn CD & bilat ADX3 ± 1 (1–10)5 ± 1 (1–15)0.05
  Mean yrs btwn CD & death25 ± 5 (11–33)29 ± 9 (12–50)0.6
Mean max tumor diameter at CD, mm6 ± 2 (1–15)1 ± 1 (1–3)0.03
Presence of macroadenoma at CD3 (6)0 (0)0.2
EBRT prior to bilateral ADX20 (43)5 (12)0.005
Multiple TSS ops prior to bilat ADX13 (28)11 (27)1.0
Indication for bilat ADX
  Severe CD w/no radiographic evidence of pituitary tumor11 (23)14 (34)0.4
  Severe CD status after hypophysectomy2 (4)4 (10)0.6
  Severe CD requiring rapid control of hypercortisolism14 (30)13 (32)0.8
  Other, unspecified, unknown20 (43)10 (24)0.08

Values are presented as the number of patients (%) unless indicated otherwise. Mean values are presented as the mean ± SEM (range). Boldface type indicates statistical significance.

Detailed Clinical History

Clinical follow-up for patients diagnosed with NSS was significantly longer (23 years vs 8 years, p < 0.0001, Table 2). Extensive chart review was conducted for clinical complications of hypercortisolism; many were noted, but only myopathy was significantly different, with a markedly higher prevalence among patients who did not experience progression (25% vs 68%, p = 0.001; Table 2). Cushingoid skin changes were noted in a majority of patients, but prototypical CD complications were infrequent and comparable between the groups (Table 2). Similarly, no major medical comorbidity was significantly different, including stroke, myocardial infarction, hypertension, osteoporosis, depression/anxiety/psychosis, obesity, or Type 2 diabetes/metabolic syndrome (Table 2).

TABLE 2.

Detailed clinical history

VariableNSS (n = 47)Non-NSS (n = 41)p Value
Mean yrs of post-bilat ADX follow-up23 ± 2 (2–58)8 ± 1 (1–42)<0.0001
Clinical complications of CD
  Myopathy12 (25)28 (68)0.001
  Cushingoid skin changes29 (62)30 (73)0.9
  Visual field deficit*3 (6)1 (2)0.4
  Apoplexy3 (6)1 (2)0.4
  Nonsurgical DI5 (11)3 (7)0.5
  Cataracts7 (15)2 (5)0.1
Medical comorbidities
  Stroke3 (6)1 (2)0.4
  Myocardial infarction2 (4)2 (5)0.9
  Hypertension17 (36)21 (51)0.2
  Osteoporosis20 (43)21 (51)0.4
  Depression/anxiety/psychosis18 (38)19 (46)0.4
  Obesity23 (49)28 (68)0.06
  Type 2 diabetes/metabolic syndrome11 (23)14 (34)0.3
  A1c§6.87.10.7
Hormonal replacement therapies
  Glucocorticoid47 (100)41 (100)1.0
  Mineralocorticoid47 (100)41 (100)1.0
  Thyroid24 (51)23 (56)0.6
  Gonadal26 (55)23 (56)0.9
Antihypercortisolism therapies
  Ketoconazole5 (11)10 (24)0.09
  Dopamine agonist2 (4)4 (10)0.3
  Somatostatin analog2 (4)4 (10)0.3
Neurosurgical complications
  DI7 (15)7 (17)0.8
  Panhypopituitarism6 (13)4 (10)0.7
  CSF leak, <30 days1 (2)1 (2)0.9
  CSF leak, >30 days0 (0)0 (0)0.9
  New postop visual field deficit2 (4)1 (2)0.6
  Hemorrhage requiring reop0 (0)1 (2)0.9
  Wound infection0 (0)0 (0)
  Meningitis0 (0)0 (0)
Mortality
  Overall (all cause)9 (19)8 (20)1.0
  Pituitary carcinoma2 (4)0 (0)0.5
  Tumor invasion1 (2)0 (0)0.9

DI = diabetes insipidus.

Values are presented as the number of patients (%) unless indicated otherwise. Mean values are presented as the mean ± SEM (range). Boldface type indicates statistical significance.

Mass effect.

Pre-bilateral ADX and not a consequence of TSS.

Body mass index > 30 kg/m2.

Values are the mean of individual highs.

Medical treatment histories were reviewed in detail, including both the need for hormonal replacement and any antitumor medications trialed. Glucocorticoid and mineralocorticoid replacement therapies were required at some point during the course of treatment for all patients; however, additional thyroid or gonadal supplementation was required in half of the patients in both groups (Table 2). Inhibitors of glucocorticoid synthesis and pituitary tumor–directed medical therapies were infrequently employed prior to bilateral ADX, and there were no significant associations between trials of ketoconazole, dopamine agonists, or somatostatin analogs and tumor progression (11% vs 24%, p = 0.09; 4% vs 10%, p = 0.3; and 4% vs 10%, p = 0.3, respectively; Table 2).

Neurosurgical complications were uncommon and were similarly distributed between the groups (Table 2). Postoperative diabetes insipidus (15% vs 17%, p = 0.8) and panhypopituitarism (13% vs 10%, p = 0.7) were the most frequently observed, with rare reports of CSF leak (2% vs 2%, p = 0.9), new visual field deficit (4% vs 2%, p = 0.6), or postoperative hemorrhage (0% vs 2%, p = 0.9; Table 2). All-cause mortality during the total follow-up period was 1-in-5 in both groups (19% vs 20%, p = 1.0); however, mortality due to malignant transformation into pituitary carcinoma or direct tumor invasion was only observed among NSS patients (4% vs 0%, p = 0.5; 2% vs 0%, p = 0.9; Table 2). Kaplan-Meier analysis did not demonstrate a survival advantage in either group (Fig. 1).

FIG. 1.
FIG. 1.

Kaplan-Meier graph comparing 20-year overall survival in patients who developed NSS versus those who did not after bilateral adrenalectomy (BAX). Figure is available in color online only.

Laboratory and Pathological Analyses

As available, laboratory data were reviewed from the time of CD diagnosis, as well as the time of bilateral ADX. Diagnostic study results for CD were not significantly different between the groups; however, a trend toward higher serum ACTH and cortisol concentrations at CD diagnosis was noted among patients who progressed to NSS (77 vs 37 pg/ml, p = 0.3; and 29 vs 24 mg/dl, p = 0.1, respectively; Table 3). Differences at the time of bilateral ADX were similarly nonsignificant, with a less marked trend toward elevation among NSS patients (100 vs 86 pg/ml, p = 0.7; and 27 vs 25 μg/dl, p = 0.5; Table 3).

TABLE 3.

Laboratory analysis

VariableNSS (n = 12)Non-NSS (n = 23)p Value
Laboratory studies at CD diagnosis
  Serum ACTH, pg/ml77 ± 53 (4–293)37 ± 30 (4–180)0.3
  Serum cortisol, µg/dl29 ± 3 (14–45)24 ± 2 (3–41)0.1
  Positive suppression test4 (33)7 (30)0.9
  Positive CRH stimulation test3 (25)7 (30)0.7
Laboratory studies at bilat ADX
  Serum ACTH, pg/ml100 ± 40 (4–234)86 ± 12 (4–121)0.7
  Serum cortisol, µg/dl27 ± 3 (6–46)25 ± 2 (3–36)0.5

CRH = corticotropin-releasing hormone.

Values are presented as the number of patients (%) unless indicated otherwise. Mean values are presented as the mean ± SEM (range).

Pituitary tumor pathology reports were reviewed when available (n = 47) with respect to both detailed immunohistochemical analysis and other abnormal findings. No significant differences were observed in staining pattern, with approximately 1-in-2 tumors demonstrating abnormal ACTH staining in both groups, as well as rare findings of abnormally increased chromogranin, mutated p53, or other anterior pituitary hormones (Table 4). Similarly, Crooke's hyaline change was frequently observed, as were diffuse abnormal cytokeratin expression and periodic acid–Schiff positivity, but without significant differences (Table 4).

TABLE 4.

Pathological analysis

VariableNSS (n = 22)Non-NSS (n = 25)p Value
Abnormal immunohistochemical staining
  ACTH22 (100)25 (100)0.9
  Chromogranin3 (14)4 (16)0.8
  Mutated p531 (5)1 (4)0.9
  Prolactin1 (5)3 (12)0.2
  Thyroid-stimulating hormone1 (5)2 (8)0.5
  Growth hormone0 (0)1 (4)0.3
  Follicle-stimulating hormone0 (0)2 (8)0.5
  Luteinizing hormone0 (0)2 (8)0.5
  Alpha subunit glycoprotein0 (0)1 (4)0.3
  CAM-5.20 (0)0 (0)
Other abnormal pathological findings
  Crooke's hyaline change5 (23)8 (32)0.7
  Periodic acid–Schiff positivity2 (9)5 (20)0.2
  Diffuse cytokeratin expression1 (5)1 (4)0.9

Non–p values are presented as the number of patients (%).

EBRT

Indication for EBRT prior to bilateral ADX differed between the groups. Patients who eventually developed NSS predominantly underwent treatment for tumor recurrence (70% vs 0%, p = 0.02; Table 5), compared with exclusive treatment of persistent CD in those who did not experience progression (30% vs 100%, p = 0.008; Table 5). Complications of EBRT were nonsignificant, with one secondary meningioma in each group (5% vs 20%, p = 0.9), and 2 reports of optic neuropathy in the NSS group (10% vs 0%, p = 0.5); no case of symptomatic radiation necrosis was documented in either cohort (Table 5).

TABLE 5.

External-beam radiation therapy prior to bilateral adrenalectomy

VariableNSSNon-NSSp Value
History of EBRT20/47 (43)5/41 (12)0.0005
  Treatment of persistent CD6 (30)5 (100)0.008
  Treatment of tumor recurrence14 (70)0 (0)0.02
EBRT complications
  Radiation-associated meningioma1 (5)1 (20)0.9
  Radiation-associated optic neuropathy2 (10)0 (0)0.5
  Symptomatic radiation necrosis0 (0)0 (0)

Values are presented as the number of patients (%). Boldface type indicates statistical significance.

Nelson-Salassa Syndrome

Patients who developed NSS experienced progression on average 3 years after bilateral ADX; the mean age at the time of NSS diagnosis was 38 years (Table 6). Serum ACTH concentrations were markedly elevated, with a mean value of 690 pg/ml, and follow-up MRI studies demonstrated mean and median tumor growth rates of 7 mm/yr and 3 mm/yr, respectively, in NSS patients (range 0.5–21 mm/yr). Classic clinical symptoms of NSS were uncommon: 4 patients (9%) with radiographic NSS developed both hyperpigmentation and visual field deficit, and hyperpigmentation occurred without visual field deficit in an additional 11 (23%), while the remaining 32 patients (68%) remained clinically asymptomatic, despite radiographic tumor progression (Table 6).

TABLE 6.

Characteristics patients with NSS

VariableNSS (n = 47)
Mean age at NSS diagnosis, yrs38 ± 3 (27–73)
Mean yrs btwn bilat ADX & NSS3 ± 2 (1–8)
Mean serum cortisol at NSS, µg/dl20 ± 5 (1–31)
Mean serum ACTH at NSS, pg/ml690 ± 177 (121–2100)
Tumor growth rate post-bilat ADX, mm/yr
  Mean7 ± 6 (0.5–21)
  Median3
Clinical NSS*4 (9)
Hyperpigmentation alone11 (23)
Asymptomatic tumor progression32 (68)
Treatment of NSS
  SRS12 (26)
    Treatment success10 (83)
    Treatment failure2 (17)
  Revision TSS2 (4)
  Expectant management33 (70)

Values are presented as the number of patients (%) unless indicated otherwise.

Hyperpigmentation, new post-ADX visual deficit, and radiographic tumor progression.

Tumor control.

Further progression.

Multivariate Analysis

Multivariate analysis was performed using the 3 independent variables that were significantly associated with progression to NSS: age, tumor size, and need for EBRT, particularly to treat tumor recurrence prior to bilateral ADX. Clinical history including young age and large tumor size, young age and history of EBRT, or large tumor size and history of EBRT respectively carried 74%, 71%, and 83% probabilities of correctly predicting progression to NSS, which was increased to 85% given congruent findings in all 3 variables (Table 7).

TABLE 7.

Multivariate analysis

VariableProbability of Progression to NSS*p Value
Positive parameters
  Age <40 yrs, tumor size ≥5 mm74%0.04
  Age <40 yrs, history of EBRT71%0.05
  Tumor size ≥5 mm, history of EBRT83%0.03
  Age <40 yrs, tumor size ≥5 mm, history of EBRT85%0.03

Boldface type indicates statistical significance.

Percentages reflect the probability of accurately predicting NSS, given the findings on the left.

Excluded Cohort

Of the 214 excluded patients, 5-year follow-up data were available for 188 (88%), at which point 8 deaths (4%) had been observed. Among these individuals, 4 deaths were attributable to unrelated primary malignancies, 2 were due to myocardial infarctions in patients with established coronary artery disease, 1 was a consequence of postoperative intraabdominal abscess precipitating severe sepsis, and 1 cause of death was not documented. Of note, no deceased patients in the excluded cohort had evidence of NSS.

Discussion

Refractory CD is a challenging neurosurgical and neuroendocrine entity, and bilateral ADX often represents the last line of defense for patients requiring definitive therapy and provides rapid control of symptomatic hypercortisolism when other modalities have failed. Among the potential complications of bilateral ADX, NSS is perhaps the most feared, in part because of the impending threat to adjacent neurological structures, including the visual apparatus, but also as it indicates treatment failure in a patient who has frequently exhausted available resources.3,10,36 Historically, the syndrome has been defined by the findings noted first by Nelson and colleagues34 and subsequently by Salassa and colleagues41 in postbilateral ADX patients, including cutaneous hyperpigmentation, markedly increased serum ACTH concentration, and visual field deficits attributable to a recurrent pituitary adenoma (Fig. 2). We present what is, to our knowledge, the longest follow-up series of patients with NSS, with thorough radiographic and clinical follow-up demonstrating that NSS is at once more prevalent and—in the majority of patients—more indolent than previously estimated.

FIG. 2.
FIG. 2.

Classic clinical NSS triad of cutaneous hyperpigmentation of the face and forearms (A and B) and visual field deficit (C) attributable to a recurrent pituitary macroadenoma (D) in the setting of a previous bilateral ADX. Figure is available in color online only.

Characterizing NSS

In the current patient cohort, progression to NSS was documented in 53%; this exceeds the upper limit of preceding series, which observed NSS in 8%–47% of patients who underwent bilateral ADX.1,3,10,13,14,18,26,36 Although this increased incidence is in part due to improvements in imaging technology and disease recognition, a fraction is also likely attributable to our diagnostic criteria, which are more inclusive and rigorously defined than those in some earlier studies. Additionally, other recent series have excluded patients who underwent pituitary EBRT prior to bilateral ADX.1 A consensus regarding diagnostic criteria for NSS has not been reached, with previous authors recommending various combinations of radiographic and biochemical parameters as possible definitions.1,3,36 By design, our study excluded biochemical criteria, including serum cortisol and ACTH concentrations; although numerous authors have identified abnormalities in these laboratory parameters as diagnostic, a clear threshold or clinically meaningful range has not been identified for either, and multiple studies—including, in retrospect, our own results—have reported equivocal findings.1,4,21,22,33,36,37,42 Rather, we selected an isolated radiographic criterion, with a 2-mm threshold to avoid including false positives attributable to differences in gantry angle or slice location between MRI studies. Despite these conservative measures in study design, we found radiographic evidence of progression to NSS in the majority of postbilateral ADX patients.

In our analysis, age, tumor size, and history of EBRT were the only outcomes significantly associated with development of NSS—including an extensive array of clinical, laboratory, pathological, and treatment outcomes, many of which were thought to predict NSS in previous analyses (Tables 15).1–3,10,36 Although not universally observed, young age at CD diagnosis is perhaps the most frequently reproduced predictor of NSS; correspondingly, we recommend that patients presenting in their 4th decade of life or younger be considered for earlier and closer surveillance for NSS—particularly within the first 5 years after bilateral ADX (Fig. 3).1,11,22,36 We also reproduced significant associations between a shorter time course from TSS to bilateral ADX—and, correspondingly, a younger age at bilateral ADX—with the development of NSS, underscoring the general principle that a more aggressive primary disease is more likely to progress.1 This relationship finds further support in our novel observation that larger adenomas at the time of CD diagnosis are predictive of NSS. Although laboratory studies were not found to be predictors of progression in our cohort, the observation of significantly elevated ACTH at the time of NSS diagnosis confirms that serum studies can provide a useful diagnostic adjunct in cases where radiographic findings are equivocal, or perhaps in a patient who cannot undergo MRI but is suspected to have NSS.

FIG. 3.
FIG. 3.

Management algorithm depicting graphically a simplified version of our institution's prototypical practice for management of CD and NSS, which is further tailored to the needs of the individual patient.

EBRT and NSS

The relationship between EBRT and NSS is nuanced, and the contradictory findings noted throughout the preceding literature demand closer examination. Several prior analyses have claimed a protective effect associated with pituitary EBRT, most prominently the series published by Gil-Cárdenas et al., demonstrating an absolute risk reduction of 30% with EBRT at time of bilateral ADX in a series of 25 patients who underwent TSS and bilateral ADX for treatment of CD.7 Similar results had previously been reported by Jenkins et al. in a series of 46 patients,12 with a 25% absolute risk reduction after EBRT; numerous small series or review articles have touted a similar benefit.3,4,8,35,36

Notwithstanding, these findings are quite controversial, and frequent progression to NSS after EBRT has been cited by many authors—starting with Salassa and colleagues' series, in which one of his 5 patients developed NSS despite undergoing previous radiation therapy.41 Other authors have found comparable progression rates between patients who underwent radiotherapy and those who did not—including Moore and colleagues,30 who observed NSS in approximately 10% of both groups in a study of 120 postbilateral ADX CD patients—and numerous studies have either failed to find a significant protective effect associated with EBRT or noted frequent progression despite treatment.2,19,27,28,37,42 In part, the present results support this conclusion; more specifically, when examining the 11-patient subgroup that received treatment for persistent CD, 6 developed NSS, while 5 did not (Table 5).

Perhaps more importantly, when indication is taken into consideration, our perspective on the significance of a history of EBRT becomes more clearly resolved: among the patients who experienced progression to NSS, 70% underwent EBRT for pituitary tumor recurrence prior to bilateral ADX, whereas 100% of the patients who did not experience progression were treated for persistent CD. Two possible explanations underlie these findings. In the first scenario, one can argue that the patients who experienced recurrence received EBRT and whose tumors later progressed were treated with radiation therapy too late in their disease course to definitively halt progression to NSS. In the second, recurrence is a marker for more aggressive tumor biology, which in turn predicts progression, despite EBRT. Although a preceding study did not show elevated Ki-67 in tumors that progressed to NSS, reality may in fact reflect aspects of each hypothesis, with patients with refractory CD falling into 2 phenotypic subtypes characterized by tumor behavior: less aggressive tumors that are unlikely to progress, but that may benefit from EBRT, particularly in the setting of persistent CD; and more aggressive tumors that are highly likely to progress to NSS, regardless of EBRT.1

Tumor Behavior and Surveillance Recommendations

Trends in the clinical characteristics of NSS patients in our series lend further support to this theory (Table 6). Although we observed a mean tumor growth rate of 7 mm/yr in NSS patients, the median was markedly lower at 3 mm/yr (range 0.5–21 mm/yr), suggesting a right-skew distribution—with most NSS patients demonstrating slow growth, while a smaller number of highly aggressive outliers progressed rapidly. In parallel, only a small subset of the patients whom we retrospectively diagnosed with NSS had come to clinical attention and received treatment in the form of SRS or further pituitary surgery. Taken together, these findings support the hypothesis that, although NSS is highly prevalent after bilateral ADX for CD, only a small fraction of patients with radiographic progression harbor an aggressive recurrence that is likely to produce clinical symptoms or require intervention. Notwithstanding, further study is required, both to evaluate this concept in more rigorous detail and to identify potential markers for predicting tumor behavior—particularly given the overwhelmingly negative clinical, laboratory, and pathological findings of the present study.

This combination of a highly prevalent disease sequela with a low incidence of symptoms invites speculation regarding optimal surveillance strategies after bilateral ADX, as well as treatment in the event of NSS diagnosis. Post–bilateral ADX pituitary screening protocols vary by institution, although it is generally agreed that pituitary MRI should be completed within the 1st year and carried out on at least a biannual basis for life.1–3,10,36 However, the possibility that NSS comprises 2 distinct tumor phenotypes and the correspondingly high likelihood of MRI identifying asymptomatic tumor progression in patients who are unlikely to develop clinical symptoms, calls the necessity of this practice into question—particularly in lower risk patients.

Of particular interest to our discussion of surveillance recommendations are the results of the multivariate analysis. These show that, for patients who present with congruent parameters in the 3 domains that were independently associated with NSS—young age, large tumor size, and history of EBRT—the probability of tumor progression is predicted at 71%–85% (Table 7). For these individuals, close postoperative follow-up is more clearly indicated, particularly given our parallel finding that progression is more likely to occur early after bilateral ADX, which echoes preceding analyses demonstrating very rapid progression in a subpopulation of NSS patients, with up to 20% developing NSS in the 1st year and 35% within 2 years.1,3

Treatment Practices and Recommendations

The question of whether to treat once NSS has declared itself radiographically presents a final point of debate, particularly given the ongoing improvements in MRI technology, which are increasingly more likely to detect evidence of asymptomatic progression on surveillance imaging.43 At its worst, NSS has the potential to precipitate severe and debilitating symptoms via involvement of the cranial nerves and cavernous sinus, with reports documenting blindness, bilateral third nerve palsy, and other related deficits from disease progression.1,3,36 Furthermore, although the finding was not significant, our analysis and previous studies have suggested a trend toward increased all-cause mortality and a shorter interval from bilateral ADX to death in patients with NSS, although the mechanism driving this is not clinically apparent at present, and requires further evaluation in a larger, prospective study.1–3,10,36

With this in mind, many authors have advocated immediate intervention, with Kemink and colleagues12 demonstrating that, in a series of 15 patients with CD who underwent bilateral ADX, of the 8 who were initially watched following NSS diagnosis, 6 went on to require repeat TSS.22 Still others have recommend close clinical followup, reserving intervention for the onset of symptoms, particularly given the heightened risks of repeat surgery in patients who had potentially undergone radiosurgery—including CSF leak, hemorrhage, or worsening pituitary dysfunction.1,2,36 Given our finding that the majority of patients with radiographic NSS never develop clinically meaningful symptoms—as well as the possibility that NSS patients may be divisible into 2 phenotypic subgroups stratified by tumor aggressiveness—we concur that expectant management is a reasonable option for the majority of asymptomatic patients. Preliminarily, in the absence of symptoms, we suggest as treatment thresholds either 5 mm of tumor growth on a single scan or continued tumor growth on 2 separate imaging studies; however, further study is clearly required to better interrogate this nuanced question and establish more definitive recommendations.

Although the most well studied strategies for management of NSS are TSS and SRS, a range of medications has been trialed, including dopamine agonists, somatostatin analogs, temozolomide, sodium valproate, and PPAR-γ (per-oxisome proliferator-activated receptor γ) agonists.5,15–17,20,23,29,31,32,36,38 Bromocriptine and cabergoline have been shown to decrease plasma ACTH levels and induce adenoma remission in isolated studies, but those findings have not been consistently reproduced.5,36,44 Pasireotide was trialed in a single patient with refractory NSS that failed both salvage surgery and SRS; tumor size was reduced and ACTH levels decreased, but the agent has not yet been trialed more broadly.16 Temozolomide was similarly attempted in a single NSS patient, who responded very well over 4 cycles with respect to tumor volume and ACTH level, but treatment was discontinued after CSF rhinorrhea and otorrhea developed and progressed to bacterial meningitis.31 Sodium valproate was studied in 2 trials of 10 and 11 NSS patients, as well as various preceding reports; ACTH levels were noted to decline during treatment, but long-term outcomes have been broadly inconclusive, with no clinical benefit noted, and ACTH levels returning to pretreatment levels weeks after the agent was discontinued.6,20 Rosiglitazone was trialed in 7 NSS patients, due to its efficacy in murine models and the established abundance of PPAR-γ receptors in human CD adenomas; unfortunately, no decrease in ACTH was noted, although this may be attributable to an inadequate dose of the study drug.9,32

At best, these isolated reports demonstrate limited success, and at present we have no institutional experience against which to compare them. Correspondingly, although we remain hopeful for the possibility of adding an effective medical therapy to the NSS armamentarium in the future, given the lack of durable tumor control for any studied agent thus far, we continue to recommend surgical or radiosurgical modalities as the standard of care in symptomatic or persistent NSS.

Although revision TSS or craniotomy has long been considered the standard of care for NSS, SRS in the present and several preceding studies has been compellingly successful, with tumor control in 83% in the present series—a marked improvement on the widely varying rates of 10%–80% quoted in modern surgical series.10,24,25,36,37,39,45,46 At present, our institutional practice is to perform SRS for symptomatic NSS, with consideration given to prophylactic SRS in those individuals who have significant residual pituitary tumors at the time of bilateral ADX or marked pituitary tumor growth at follow-up. However, both our experience and the broader literature on NSS remain limited by small sample sizes and the lack of randomized evidence, and treatment should be tailored to the clinical history and imaging findings of the individual patient.

Study Limitations

Our study is subject to several general limitations, including retrospective analysis, small cohort sizes, inconsistent reporting of subjective clinical outcomes, and incomplete data on patients whose care was managed outside our institution prior to bilateral ADX. A further specific limitation is the large number of excluded patients who had undergone bilateral ADX, which presents a source of potential bias. More specifically, the large exclusion may have influenced our estimate of the incidence of NSS; additionally, it is imaginable that the excluded population hid within it a significant number of patients who developed symptomatic NSS and died prior to follow-up imaging, falsely underestimating our impression of the overall disease aggressiveness.

The preceding concern is, in large part, attributable to the availability of MRI technology during the routine follow-up period for many of the early patients in the study who correspondingly never underwent imaging. Consideration was given to the possibility of excluding all patients prior to the advent of widely accessible MRI within our institution; however, doing so would have removed a considerable number of patients from our analysis. Given the overall rarity of NSS and the paucity of large series in the literature, it was our judgment that publishing a larger series subject to this minor source of bias was substantially preferable to excluding a population that we believe contributes valuably to our understanding of this rare disease.

With respect to the possibility of a missed cohort of NSS patients who developed aggressive disease, our secondary review of the excluded patient population demonstrated a very low early mortality. As such, although this finding does not definitively exclude the possibility of undiagnosed NSS among those excluded from the study, it does support our preceding conclusion that, where present, NSS has an overwhelmingly benign natural history.

Finally, our study design was such that the minimum follow-up for inclusion was 2 years, yet our data demonstrated a mean time to progression of 3 years, suggesting that our estimates may underrepresent the true disease incidence. Despite these shortcomings, we believe that our new data may lead to novel insights regarding the character of an elusive and poorly understood entity.

Conclusions

To our knowledge, we report the longest series of NSS patients, with extensive radiographic and clinical followup. Chiefly, we found that, although the incidence of NSS may be higher than previously estimated, clinically significant consequences are uncommon, and most NSS patients experience a relatively indolent natural history. Our data also suggest that NSS patients may fall broadly into 2 subgroups, stratified by tumor aggressiveness—with young age at CD or bilateral ADX, larger tumor size at CD, or a history of EBRT marking more aggressive phenotypes, and therefore patients who are most likely to experience tumor progression to NSS and potentially require intervention. Notwithstanding, in all patients NSS represents an important and potentially life-threatening neurosurgical entity, warranting heightened surveillance and consideration for treatment, particularly in the face of clinical symptoms or aggressive tumor behavior.

Afterword—Remembering Dr. Robert Salassa

Robert M. Salassa, MD (1914–1992), was an endocrinologist on staff at Mayo Clinic from 1949 to 1984 (Fig. 4). In 1951, before the era of modern transsphenoidal surgery, Salassa and colleagues wrote about the role for subtotal adrenalectomy for the treatment of Cushing syndrome.40 By 1958, Salassa had collected 5 patients with pituitary-dependent Cushing syndrome who had experienced diffuse hyperpigmentation and aggressive pituitary tumor growth following bilateral adrenalectomy. He wanted to be certain about this association before publishing. However, it was in July 1958 that Nelson and colleagues published their single case of this association in the New England Journal of Medicine;34 Salassa and colleagues published their case series the following year.41 Salassa wrote in the conclusion:

FIG. 4.
FIG. 4.

Robert M. Salassa, MD, of the Mayo Clinic Department of Endocrinology, who reported the second case and first series of Nelson-Salassa syndrome, which consistent of five patients, published in 1959. Copyright Division of Endocrinology, Mayo Clinic. Published with permission. Figure is available in color online only.

The observations in this small group of patients are disquieting, since they suggest that adrenalectomy occasionally may enhance the growth of pituitary tumors. Further observation of a larger number of patients with a long follow-up period is needed before the magnitude of the hazard of a progressive pituitary tumor can be accurately evaluated. Similar observations on a group of patients with coexisting Cushing's syndrome and pituitary tumor who are treated by pituitary irradiation or surgical removal of the tumor, or both, are needed before the relative merits of treatment directed at the pituitary, on the one hand, and of subtotal or total adrenalectomy, on the other, can be evaluated.

The disorder became known as Nelson's syndrome; however, at Mayo Clinic, it has always been referred to as “Nelson-Salassa syndrome.”

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Van Gompel, Graffeo, Perry, Young. Acquisition of data: Graffeo, Perry, Carlstrom, Meyer, Atkinson, Erickson, Nippoldt, Young, Pollock. Analysis and interpretation of data: Graffeo, Perry. Drafting the article: Graffeo. Critically revising the article: Van Gompel, Graffeo, Perry, Erickson, Young, Pollock. Reviewed submitted version of manuscript: Graffeo. Approved the final version of the manuscript on behalf of all authors: Van Gompel. Statistical analysis: Graffeo. Administrative/technical/material support: Graffeo. Study supervision: Van Gompel.

Supplemental Information

Previous Presentations

Components of this paper were presented at the 83rd American Association of Neurological Surgeons Scientific Meeting May 2–6, 2015, in Washington, DC, and the North American Skull Base Society 26th Annual Meeting, February 12–14, 2016, Scottsdale, AZ.

References

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    Casulari LA, Naves LA, Mello PA, Pereira Neto A, Papadia C: Nelson's syndrome: complete remission with cabergoline but not with bromocriptine or cyproheptadine treatment. Horm Res 62:300305, 2004

    • Search Google Scholar
    • Export Citation
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    Dornhorst A, Jenkins JS, Lamberts SW, Abraham RR, Wynn V, Beckford U, et al.: The evaluation of sodium valproate in the treatment of Nelson's syndrome. J Clin Endocrinol Metab 56:985991, 1983

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    • Export Citation
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    Gil-Cárdenas A, Herrera MF, Díaz-Polanco A, Rios JM, Pantoja JP: Nelson's syndrome after bilateral adrenalectomy for Cushing's disease. Surgery 141:147152, 2007

    • Search Google Scholar
    • Export Citation
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    Hawn MT, Cook D, Deveney C, Sheppard BC: Quality of life after laparoscopic bilateral adrenalectomy for Cushing's disease. Surgery 132:10641069, 2002

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    • Export Citation
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    Heaney AP, Fernando M, Yong WH, Melmed S: Functional PPAR-γ receptor is a novel therapeutic target for ACTH-secreting pituitary adenomas. Nat Med 8:12811287, 2002

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    Kasperlik-Załuska AA, Bonicki W, Jeske W, Janik J, Zgliczyński W, Czernicki Z: Nelson's syndrome—46 years later: clinical experience with 37 patients. Zentralbl Neurochir 67:1420, 2006

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    Kasperlik-Załuska AA, Zgliczyński W, Jeske W, Zdunowski P: ACTH responses to somatostatin, valproic acid and dexa-methasone in Nelson's syndrome. Neuroendocrinol Lett 26:709712, 2005

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    Katznelson L: Sustained improvements in plasma ACTH and clinical status in a patient with Nelson's syndrome treated with pasireotide LAR, a multireceptor somatostatin analog. J Clin Endocrinol Metab 98:18031807, 2013

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    • Export Citation
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    Kelestimur F, Utas C, Ozbakir O, Selçuklu A, Kandemir O, Ozcan N: The effects of octreotide in a patient with Nelson's syndrome. Postgrad Med J 72:5354, 1996

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    • Export Citation
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    Kelly DF: Transsphenoidal surgery for Cushing's disease: a review of success rates, remission predictors, management of failed surgery, and Nelson's Syndrome. Neurosurg Focus 23:3 E5, 2007

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    • Export Citation
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    Kelly PA, Samandouras G, Grossman AB, Afshar F, Besser GM, Jenkins PJ: Neurosurgical treatment of Nelson's syndrome. J Clin Endocrinol Metab 87:54655469, 2002

    • Search Google Scholar
    • Export Citation
  • 20

    Kelly W, Adams JE, Laing I, Longson D, Davies D: Long-term treatment of Nelson's syndrome with sodium valproate. Clin Endocrinol (Oxf) 28:195204, 1988

    • Search Google Scholar
    • Export Citation
  • 21

    Kelly WF, MacFarlane IA, Longson D, Davies D, Sutcliffe H: Cushing's disease treated by total adrenalectomy: long-term observations of 43 patients. Q J Med 52:224231, 1983

    • Search Google Scholar
    • Export Citation
  • 22

    Kemink L, Pieters G, Hermus A, Smals A, Kloppenborg P: 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 79:887889, 1994

    • Search Google Scholar
    • Export Citation
  • 23

    Kurowska M, Nowakowski A, Zieliński G, Malicka J, Tarach JS, Maksymowicz M, et al.: Temozolomide-induced shrinkage of invasive pituitary adenoma in patient with Nelson's syndrome: a case report and review of the literature. Case Rep Endocrinol 2015:623092, 2015

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    • Export Citation
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  • View in gallery

    Kaplan-Meier graph comparing 20-year overall survival in patients who developed NSS versus those who did not after bilateral adrenalectomy (BAX). Figure is available in color online only.

  • View in gallery

    Classic clinical NSS triad of cutaneous hyperpigmentation of the face and forearms (A and B) and visual field deficit (C) attributable to a recurrent pituitary macroadenoma (D) in the setting of a previous bilateral ADX. Figure is available in color online only.

  • View in gallery

    Management algorithm depicting graphically a simplified version of our institution's prototypical practice for management of CD and NSS, which is further tailored to the needs of the individual patient.

  • View in gallery

    Robert M. Salassa, MD, of the Mayo Clinic Department of Endocrinology, who reported the second case and first series of Nelson-Salassa syndrome, which consistent of five patients, published in 1959. Copyright Division of Endocrinology, Mayo Clinic. Published with permission. Figure is available in color online only.

  • 1

    Assié G, Bahurel H, Coste J, Silvera S, Kujas M, Dugué MA, et al.: Corticotroph tumor progression after adrenalectomy in Cushing's disease: a reappraisal of Nelson's syndrome. J Clin Endocrinol Metab 92:172179, 2007

    • Search Google Scholar
    • Export Citation
  • 2

    Banasiak MJ, Malek AR: Nelson syndrome: comprehensive review of pathophysiology, diagnosis, and management. Neurosurg Focus 23:3 E13, 2007

    • Search Google Scholar
    • Export Citation
  • 3

    Barber TM, Adams E, Ansorge O, Byrne JV, Karavitaki N, Wass JA: Nelson's syndrome. Eur J Endocrinol 163:495507, 2010

  • 4

    Barnett AH, Livesey JH, Friday K, Donald RA, Espiner EA: Comparison of preoperative and postoperative ACTH concentrations after bilateral adrenalectomy in Cushing's disease. Clin Endocrinol (Oxf) 18:301305, 1983

    • Search Google Scholar
    • Export Citation
  • 5

    Casulari LA, Naves LA, Mello PA, Pereira Neto A, Papadia C: Nelson's syndrome: complete remission with cabergoline but not with bromocriptine or cyproheptadine treatment. Horm Res 62:300305, 2004

    • Search Google Scholar
    • Export Citation
  • 6

    Dornhorst A, Jenkins JS, Lamberts SW, Abraham RR, Wynn V, Beckford U, et al.: The evaluation of sodium valproate in the treatment of Nelson's syndrome. J Clin Endocrinol Metab 56:985991, 1983

    • Search Google Scholar
    • Export Citation
  • 7

    Gil-Cárdenas A, Herrera MF, Díaz-Polanco A, Rios JM, Pantoja JP: Nelson's syndrome after bilateral adrenalectomy for Cushing's disease. Surgery 141:147152, 2007

    • Search Google Scholar
    • Export Citation
  • 8

    Hawn MT, Cook D, Deveney C, Sheppard BC: Quality of life after laparoscopic bilateral adrenalectomy for Cushing's disease. Surgery 132:10641069, 2002

    • Search Google Scholar
    • Export Citation
  • 9

    Heaney AP, Fernando M, Yong WH, Melmed S: Functional PPAR-γ receptor is a novel therapeutic target for ACTH-secreting pituitary adenomas. Nat Med 8:12811287, 2002

    • Search Google Scholar
    • Export Citation
  • 10

    Hornyak M, Weiss MH, Nelson DH, Couldwell WT: Nelson syndrome: historical perspectives and current concepts. Neurosurg Focus 23:3 E12, 2007

    • Search Google Scholar
    • Export Citation
  • 11

    Imai T, Funahashi H, Tanaka Y, Tobinaga J, Wada M, Morita-Matsuyama T, et al.: Adrenalectomy for treatment of Cushing syndrome: results in 122 patients and long-term follow-up studies. World J Surg 20:781787, 1996

    • Search Google Scholar
    • Export Citation
  • 12

    Jenkins PJ, Trainer PJ, Plowman PN, Shand WS, Grossman AB, Wass JA, et al.: The long-term outcome after adrenalectomy and prophylactic pituitary radiotherapy in adrenocorticotropin-dependent Cushing's syndrome. J Clin Endocrinol Metab 80:165171, 1995

    • Search Google Scholar
    • Export Citation
  • 13

    Kasperlik-Załuska AA, Bonicki W, Jeske W, Janik J, Zgliczyński W, Czernicki Z: Nelson's syndrome—46 years later: clinical experience with 37 patients. Zentralbl Neurochir 67:1420, 2006

    • Search Google Scholar
    • Export Citation
  • 14

    Kasperlik-Załuska AA, Nielubowicz J, Wisławski J, Hartwig W, Załuska J, Jeske W, et al.: Nelson's syndrome: incidence and prognosis. Clin Endocrinol (Oxf) 19:693698, 1983

    • Search Google Scholar
    • Export Citation
  • 15

    Kasperlik-Załuska AA, Zgliczyński W, Jeske W, Zdunowski P: ACTH responses to somatostatin, valproic acid and dexa-methasone in Nelson's syndrome. Neuroendocrinol Lett 26:709712, 2005

    • Search Google Scholar
    • Export Citation
  • 16

    Katznelson L: Sustained improvements in plasma ACTH and clinical status in a patient with Nelson's syndrome treated with pasireotide LAR, a multireceptor somatostatin analog. J Clin Endocrinol Metab 98:18031807, 2013

    • Search Google Scholar
    • Export Citation
  • 17

    Kelestimur F, Utas C, Ozbakir O, Selçuklu A, Kandemir O, Ozcan N: The effects of octreotide in a patient with Nelson's syndrome. Postgrad Med J 72:5354, 1996

    • Search Google Scholar
    • Export Citation
  • 18

    Kelly DF: Transsphenoidal surgery for Cushing's disease: a review of success rates, remission predictors, management of failed surgery, and Nelson's Syndrome. Neurosurg Focus 23:3 E5, 2007

    • Search Google Scholar
    • Export Citation
  • 19

    Kelly PA, Samandouras G, Grossman AB, Afshar F, Besser GM, Jenkins PJ: Neurosurgical treatment of Nelson's syndrome. J Clin Endocrinol Metab 87:54655469, 2002

    • Search Google Scholar
    • Export Citation
  • 20

    Kelly W, Adams JE, Laing I, Longson D, Davies D: Long-term treatment of Nelson's syndrome with sodium valproate. Clin Endocrinol (Oxf) 28:195204, 1988

    • Search Google Scholar
    • Export Citation
  • 21

    Kelly WF, MacFarlane IA, Longson D, Davies D, Sutcliffe H: Cushing's disease treated by total adrenalectomy: long-term observations of 43 patients. Q J Med 52:224231, 1983

    • Search Google Scholar
    • Export Citation
  • 22

    Kemink L, Pieters G, Hermus A, Smals A, Kloppenborg P: 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 79:887889, 1994

    • Search Google Scholar
    • Export Citation
  • 23

    Kurowska M, Nowakowski A, Zieliński G, Malicka J, Tarach JS, Maksymowicz M, et al.: Temozolomide-induced shrinkage of invasive pituitary adenoma in patient with Nelson's syndrome: a case report and review of the literature. Case Rep Endocrinol 2015:623092, 2015

    • Search Google Scholar
    • Export Citation
  • 24

    Laws ER Jr, Thapar K: Pituitary surgery. Endocrinol Metab Clin North Am 28:119131, 1999

  • 25

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