Repeat Endoscopic Endonasal Transsphenoidal Surgery for Residual or Recurrent Cushing’s Disease: Safety, Feasibility, and Success

Posted on May 20, 2024 by MaryO

Abstract

Purpose

The success and outcomes of repeat endoscopic transsphenoidal surgery (ETS) for residual or recurrent Cushing’s disease (CD) are underreported in the literature. This study aims to address this gap by assessing the safety, feasibility, and efficacy of repeat ETS in these patients.

Methods

A retrospective analysis was conducted on 56 patients who underwent a total of 65 repeat ETS performed by a single neurosurgeon between January 2006 and December 2020. Data including demographic, clinical, laboratory, radiological, and operational details were collected from electronic medical records. Logistic regression was used to identify potential predictors associated with sustained remission.

Results

Among the cases, 40 (61.5%) had previously undergone microscopic surgery, while 25 (38.5%) had prior endoscopic procedures. Remission was achieved in 47 (83.9%) patients after the first repeat ETS, with an additional 9 (16.1%) achieving remission after the second repeat procedure. During an average follow-up period of 97.25 months, the recurrence rate post repeat surgery was 6.38%. Sustained remission was achieved in 48 patients (85.7%), with 44 after the first repeat ETS and 4 following the second repeat ETS. Complications included transient diabetes insipidus (DI) in 5 (7.6%) patients, permanent (DI) in 2 (3%) patients, and one case (1.5%) of panhypopituitarism. Three patients (4.6%) experienced rhinorrhea requiring reoperation. A serum cortisol level > 5 µg/dL on postoperative day 1 was associated with a reduced likelihood of sustained remission.

Conclusion

Repeat ETS is a safe and effective treatment option for residual or recurrent CD with satisfactory remission rates and low rates of complications.

Introduction

Cushing’s disease (CD) arises from an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, leading to excessive endogenous glucocorticoid production [ 1 ]. The reported incidence of CD varies from 0.7 to 2.4 cases per million individuals annually [ 2 ‐ 6 ]. Hypercortisolism impacts every bodily system and is linked to increased morbidity and mortality risks [ 7 , 8 ]. Therefore, prompt CD diagnosis and management are crucial to enhance patient outcomes.
Transsphenoidal surgery remains the primary treatment for CD, and has been associated with satisfactory remission rates ranging from 65 to 94% [ 2 , 3 , 5 , 9 ‐ 11 ]. Two surgical techniques are utilized: microscopic and endoscopic approaches. While both methods are effective, studies indicate that endoscopic transsphenoidal surgery (ETS) offers higher rates of complete tumor removal and lower complication rates [ 12 ‐ 14 ]. ETS holds advantages over microscopic transsphenoidal surgery (MTS) due to superior tumor visualization, especially for laterally invasive tumors and macroadenomas [ 15 ]. Since its introduction in 1997, ETS has gained popularity and is now the standard surgical approach for managing CD [ 16 ].
Remission rates post-ETS for CD treatment range from 77 to 90% [ 17 ‐ 22 ]. Despite ETS’s technical benefits and favorable outcomes, recurrence rates for Cushing’s disease after successful ETS range between 5.6% and 22.8% [ 17 , 18 , 22 , 23 ]. Reoperating for residual or recurrent CD presents challenges due to altered surgical landmarks and scar tissue formation from previous surgeries, potentially elevating morbidity, and mortality risks [ 24 , 25 ]. Limited literature exists on the success and outcomes of repeat endoscopic transsphenoidal surgery for residual or recurrent CD. This study aims to address this gap by assessing the safety, feasibility, and efficacy of repeat ETS in patients with residual or recurrent Cushing’s disease.

Methods

Study design

This is a retrospective cohort study of repeat endoscopic transsphenoidal surgery for residual or recurrent Cushing’s disease. All patients underwent endoscopic endonasal transsphenoidal surgery by the senior author between 2006 and 2020. The study protocol was approved by the local ethics committee for clinical studies.

Patient selection

The study participants were selected based on specific inclusion and exclusion criteria. Inclusion criteria were as follows: (i) a confirmed diagnosis of Cushing’s disease, (ii) prior transsphenoidal surgery, and (iii) confirmation of residual or recurrent CD through clinical, laboratory, and/or imaging assessments. Exclusion criteria included: (i) prior craniotomy without transsphenoidal surgery, (ii) previous radiotherapy before reoperation, (iii) inaccessible clinical, laboratory, or radiological data, and (iv) follow-up duration of less than 6 months.

Diagnostic criteria

Each patient underwent thorough screening for active Cushing’s disease. An increased 24-hour urine cortisol level > 45 µg/day or a serum fasting cortisol level exceeding 1.8 µg/dl following a low-dose (2 mg) dexamethasone suppression test was deemed abnormal. Subsequently, a high-dose (8 mg) dexamethasone test was administered, and a reduction of 50% or more from the baseline value was indicative of active Cushing’s disease. Due to the technical limitations of the institution that the research has been done, late-night salivary cortisol tests were not performed. Early remission was characterized by a fasting serum cortisol level below 5 µg/dl on the 1st and 7th postoperative days. Patients displaying a serum cortisol level below 1.8 µg/dl after the low-dose dexamethasone suppression test or those requiring continued corticosteroid replacement post-surgery were considered to maintain remission. The presence of a residual adenoma on postoperative magnetic resonance imaging (MRI) confirmed residual disease.

Routine follow-up protocol

Patients were evaluated for Cushing’s disease symptoms before surgery and monitored at 6 months after surgery, as well as during annual check-ups for any changes in their condition. Fasting serum ACTH and cortisol levels were measured in the morning before surgery, on the 1st and 7th days after surgery, at the 1st, 3rd, and 6th months, and during annual follow-up appointments. Prior to surgery, all patients underwent contrast-enhanced pituitary MRI and paranasal sinus CT scans. Follow-up pituitary MRI scans were conducted on the 1st day, at 3 and 12 months after surgery, and then annually thereafter.

Data collection

Data from electronic medical records were gathered, encompassing demographic, clinical, laboratory, radiological, and operational details. Laboratory assessments comprised an anterior pituitary hormone panel (Follicle-stimulating hormone [FSH], Luteinizing hormone [LH], Thyroid-stimulating hormone [TSH], Prolactin [PRL], Growth hormone [GH]), serum electrolytes, preoperative and postoperative serum ACTH, and cortisol levels. Patient records, along with CT and MRI scans, were scrutinized to document preoperative tumor characteristics such as size, multifocality, relationship with the cavernous sinus, Hardy-Wilson classification of sellar destruction, and suprasellar extension. Tumors larger than 10 mm were classified as macroadenomas. The operational database was examined to collect data on previous surgeries, including the number and dates of prior procedures, as well as the surgical techniques utilized. Outcome measures included remission rates and surgical complications.

Statistical analysis

Statistical analysis was conducted utilizing SPSS 23.0 software (IBM, New York). Two-group comparisons were performed using Chi-square and Fisher’s exact tests for categorical variables and Student’s t-test for continuous variables. Categorical variables were presented as numbers and percentages, while continuous variables were presented as means ± SD or median [IQR]. Logistic regression was performed to investigate potential predictors linked to sustained remission. A p-value of < 0.05 was considered statistically significant.

Results

Baseline characteristics

Supplementary File 1 displays the demographic characteristics of the patient cohort.
A retrospective analysis was conducted on 190 patients who underwent a total of 212 operations for CD at our department between January 2006 and December 2020. Among them, 56 patients, comprising 65 repeat endonasal transsphenoidal surgeries due to either recurrence ( n  = 18, 27.7% ) or residual disease ( n  = 47, 72.3%), were identified. The majority of patients were female ( n  = 48, 85.7%), with a mean age of 37.6 ± 12.4 years. Of the 56 patients, 43 (76.8%) were referred from another institution. Most patients ( n  = 42, 75%) had undergone only one prior surgery, while 12 patients (21.4%) had a history of two previous surgeries, and 2 patients (3.6%) had undergone three prior surgeries before referral to our center. The average follow-up duration since the first repeat ETS was 97.2 ± 36.8 months. The mean time to recurrence was 80.2 ± 61.1 months (median 75 months, range 23.2 to 103.5 months).

Hormonal data

Table  1 depicts the preoperative and postoperative serum ACTH and cortisol levels. The average preoperative serum cortisol levels for the entire patient cohort stood at 18.7 ± 11.1 µg/dL (median 17, range 12-24.6). The median preoperative 24-hour urine free cortisol level was 237 µg/day [188.5–425.5]. On the initial postoperative day, the mean serum cortisol levels for all patients were 13.4 ± 13.8 µg/dL (median 6.4, range 1.7–21). In 46.2% of cases ( n  = 30), cortisol levels on the first postoperative day were below 5 µg/dL (< 2 µg/dL in 33.8%). A comparison of the mean preoperative and postoperative serum ACTH and cortisol levels between the groups with residual disease and recurrence is detailed in Table  1 .
Table 1

Cohort overview and comparison of recurrence and residual disease groups
variable
Total ( n  = 65)
Residual disease ( n  = 47)
Recurrence ( n  = 18)
p -value
Technique of the previous surgery
< 0.001
 MTS
40 (61.5)
36 (76.6)
4 (22.2)
 ETS
25 (38.5)
11 (23.4)
14 (77.8)
Tumor size
 Microadenoma
41 (63.1)
30 (63.8)
11 (61.1)
0.839
 Macroadenoma
24 (36.9)
17 (36.2)
7 (38.9)
Multifocality
 Unifocal
50 (76.9)
37 (78.7)
13 (72.2)
0.743
 Bifocal
15 (23.1)
10 (21.3)
5 (27.8)
Relation to cavernous sinus
 Extension
21 (32.3)
15 (31.9)
6 (33.3)
0.589
 invasion
10 (15.4)
6 (12.8)
4 (22.2)
 No relationship
34 (52.3)
26 (55.3)
8 (44.4)
Hardy-Wilson Classification
0.339
 Degrees
  I
38 (58.5)
25 (59.5)
8 (57.1)
  II
16 (24.6)
8 (19)
5 (5)
  III
6 (9.2)
6 (14.3)
1 (7.1)
  IV
5 (7.7)
3 (7.1)
0 (0)
 stage
0.443
  A
30 (46.2)
19 (45.2)
7 (50)
  b
7 (10.8)
4 (9.5)
3 (21.4)
  C
2 (3.1)
2 (4.8)
0 (0)
  D
1 (1.5)
0 (0)
0 (0)
  E
25 (38.5)
17 (40.5)
4 (28.6)
Laboratory values
 Preoperative serum ACTH (pg/mL)
182.71 ± 577.08
60.5 [37.15–104.5]
220.7 ± 675.73
83.5 ± 61.7
0.395
 Preoperative serum cortisol (µg/dL)
18.75 ± 11.16
17 [12-24.65]
19.18 ± 12.11
17.64 ± 8.39
0.621
 Postoperative serum ACTH (pg/mL)
43.29 ± 50.2
25.5 [15.8–53.7]
43.07 ± 45.42
43.94 ± 63.96
0.953
 Postoperative serum cortisol (µg/dL)
13.41 ± 13.85
6.45 [1.77–21.01]
14.62 ± 14.52
10.25 ± 11.7
0.259
POD 1 Cortisol levels
0.700
 >5 µg/dL
35 (53.8)
26 (55.3)
9 (50)
 ≤5 µg/dL
30 (46.2)
21 (44.7)
9 (50)
Tumor pathology
0.198
 ACTH + adenoma
55 (85)
40 (85.1)
15 (83.3)
 Crooke degeneration
2 (3)
1 (2.1)
1 (5.6)
 Pituitary hyperplasia
2 (3)
1 (2.1)
1 (5.6)
 Normal pituitary tissue
6 (9)
5 (10.6)
1 (5.6)
Result of reoperation
0.740
 Remission
51 (78.5)
36 (76.6)
15 (83.3)
 Residual disease
14 (21.5)
11 (23.4)
3 (16.7)
Values ​​are shown as number (%), mean ± SD or median [IQR] unless otherwise indicated
Abbreviations MTS, microscopic transsphenoidal surgery; ETS, endoscopic transsphenoidal surgery; ACTH, adrenocorticotropic hormone; POD 1, postoperative day 1

Radiological findings

In the entire case cohort, there were 41 microadenomas (63.1%) and 24 macroadenomas (36.9%). Fifteen cases (23.1%) exhibited bifocal adenomas. Adenoma extension into the cavernous sinuses, indicated by cavernous sinus wall displacement, was present in 21 cases (32.3%), while invasion into the cavernous sinuses was observed in 10 cases (15.4%). Based on the Hardy-Wilson Classification, there were 38 Grade I adenomas (58.5%), 16 Grade II adenomas (24.6%), 6 Grade III adenomas (9.2%), and 5 Grade IV adenomas (7.7%). Thirty patients (46.2%) presented with Stage A adenoma, 7 (10.8%) with Stage B adenoma, 2 (3.1%) with Stage C adenoma, 1 (1.5%) with Stage D adenoma, and 25 (38.5%) with Stage E adenoma. As indicated in Table  1 , there were no statistically significant differences between patients with residual disease and recurrence concerning radiological findings.

Surgical characteristics

A single surgeon conducted all 65 reoperations. Among these, 47 patients (72.3%) underwent repeat ETS due to residual disease, while 18 (27.7%) did so due to recurrence. The previous surgical technique was microscopic in 40 cases (61.5%) and endoscopic in 25 cases (38.5%). Microscopic transsphenoidal surgeries were exclusively performed at other institutions. There was a notable disparity between patients with residual disease and recurrence regarding the technique of the previous surgery. Residual disease occurrence following endoscopic transsphenoidal surgery was less frequent ( n  = 11/25, 44%) compared to after microscopic transsphenoidal surgery ( n  = 36/40, 90%; p  < 0.001) (Table  1 ). Immunohistochemical staining of the specimens indicated that 55 cases (85%) exhibited ACTH-positive adenoma. Nevertheless, all patients with a negative pathology at the repeat surgery had a confirmed ACTH adenoma at the first surgery. Of the 10 patients (15%) with a negative ACTH-positive adenoma pathology, two patients underwent inferior petrosal sinus sampling (IPSS) previously and were confirmed to have CD. Remaining patients did not undergo an additional inferior petrosal sinus sampling (IPSS) because all functional test results indicated a central source and MRI confirmed pituitary microadenoma in all cases. Notably, there are studies reporting that IPSS may not be required in patients with a sellar mass and a biochemical testing suggestive of CD [ 26 , 27 ]. Additionally, we also explored both sides of the pituitary and confirmed the adenoma intraoperatively. Therefore, negative pathology in the repeat surgery is most likely due to sampling error.

Outcomes

As depicted in Fig.  1 , among the 56 patients, 47 (83.9%) experienced initial remission following the first repeat ETS, while 9 (16.1%) still had residual adenoma. Within the group achieving initial remission, 44 patients (93.6%) maintained remission without the need for further surgeries, while 3 (6.4%) experienced recurrence during follow-up and required a second repeat ETS.

https://static-content.springer.com/image/art%3A10.1007%2Fs11102-024-01396-x/MediaObjects/11102_2024_1396_Fig1_HTML.png

Fig. 1

Outcomes of repeat endoscopic transsphenoidal surgery for residual or recurrent Cushing’s disease
Among the 9 patients with residual disease after the first repeat ETS, 1 (11.1%) opted to defer further treatment, 1 (11.1%) received radiotherapy, 1 (11.1%) chose adrenalectomy, and 6 (66.7%) underwent a second repeat ETS. Of the 9 patients who underwent a second repeat ETS due to residual disease or recurrence, 4 (44.4%) sustained remission, 5 (55.6%) still had residual disease, but 3 of them deferred further treatment, 1 received radiotherapy, while 1 achieved remission after adrenalectomy. Overall, 78.5% ( n  = 51) of the entire case cohort achieved remission following repeat ETS. Representative cases are presented in Fig.  2 .

https://static-content.springer.com/image/art%3A10.1007%2Fs11102-024-01396-x/MediaObjects/11102_2024_1396_Fig2_HTML.png

Fig. 2

Case 1: Preoperative and postoperative magnetic resonance imaging (MRI) scans of a 49-year-old female who underwent repeat endoscopic transsphenoidal surgery (ETS) due to recurrent Cushing’s disease and achieved remission. The patient underwent initial surgery 14 years ago at an outside institution. Preoperative T2 ( A ), and T1 contrast-enhanced ( B ) MRI scans demonstrate a right-sided pituitary adenoma. Postoperative T2 ( C ), and T1 contrast-enhanced ( D ) MRI scans demonstrate total resection of the adenoma. Case 2: Preoperative and postoperative magnetic resonance imaging (MRI) scans of a 53-year-old female who underwent repeat endoscopic transsphenoidal surgery (ETS) due to recurrent Cushing’s disease and achieved remission. The patient underwent initial surgery 3 years ago at an outside institution. Preoperative T2 ( E ), and T1 contrast-enhanced ( F ) MRI scans demonstrate a left-sided pituitary adenoma, in close relation to ICA. Postoperative T2 ( G ), and T1 contrast-enhanced ( H ) MRI scans demonstrate total resection of the adenoma
Transient diabetes insipidus (DI) developed in 5 patients (7.6%), while 2 (3%) experienced permanent DI following repeat ETS. Intraoperative cerebrospinal fluid (CSF) leak occurred in 20 operations (30.7%). Three patients (4.6%) developed rhinorrhea and required reoperation. Five patients (7.6%) developed prolactin deficiency, 3 patients (4.6%) had GH deficiency, and another 3 patients (4.6%) had TSH deficiency requiring thyroxine replacement. Four patients (6.2%) had combined deficiencies in TSH, FSH, LH and prolactin, while one patient (1.5%) developed panhypopituitarism following the second repeat ETS.

Factors predisposing to unsuccessful repeat endoscopic transsphenoidal surgery

Among the 42 patients who underwent repeat ETS for residual disease, 9 (21.4%) still had residual disease after the first repeat ETS. We conducted a multivariable logistic regression analysis to explore potential risk factors for unsuccessful repeat ETS. However, the analysis did not reveal any significant association between the success of repeat ETS and factors such as extension or invasion into cavernous sinuses, sellar or parasellar extension, or tumor size (Supplementary File 1 ).

Potential predictors of sustained remission

We conducted a multivariable logistic regression analysis to investigate possible predictors of sustained remission. The variables included in the analysis are detailed in Table 5. The results indicated that having a serum cortisol level exceeding 5 µg/dL on postoperative day 1 was linked to a decreased likelihood of achieving sustained remission (odds ratio [OR] 0.09, 95% confidence interval [CI] 0.01–0.52, p  = 0.006) (Table  2 ).
Table 2

Logistic regression analysis of potential predictors for continued remission
variable
OR (95% CI)
p -value
Age
1.003 (0.94–1.06)
0.913
Gender
 Female
Reference
 times
0.43 (0.06–2.88)
0.387
Indication for repeat ETS
 Residual disease
Reference
 Recurrence
1.2 (0.25–5.68)
0.812
Tumor size
 Microadenoma
Reference
 Macroadenoma
0.94 (0.18–4.79)
0.948
Relation to cavernous sinus
 No relation
Reference
 Extension invasion
0 (0)
0.999
Hardy-Wilson Classification
 Degrees
  I-II
Reference
  III-IV
3.2 (0.3-34.06)
0.334
 stage
  AC
Reference
  EN
0 (0)
0.999
POD 1 Cortisol levels
 ≤5 µg/dL
Reference
 >5 µg/dL
0.09 (0.01–0.52)
0.006
Abbreviations ETS, endoscopic transsphenoidal surgery; POD 1, postoperative day 1

Discussion

Transsphenoidal surgery remains the established standard for treating Cushing’s disease, with demonstrated remission rates ranging from 65 to 94%, contingent upon the surgeon’s expertise and remission criteria [ 2 , 3 , 5 , 9 ‐ 11 ]. The advent of endoscopic techniques has significantly augmented this approach, offering greater visibility, reduced nasal trauma, and shorter hospital stays [ 16 , 25 , 28 , 29 ]. While the effectiveness of ETS in managing CD is well-documented, literature on its efficacy in treating residual or recurrent cases is limited. Our study addresses this gap by assessing the safety, feasibility, and outcomes of repeat ETS for patients with persistent or recurrent Cushing’s disease.
In our study, 56 patients underwent 65 repeat ETS procedures for residual or recurrent Cushing’s disease. Mean follow-up duration was 97.2 ± 36.8 months, which is one of the longest follow-up durations that has been reported following repeat endoscopic transsphenoidal surgery [ 5 , 30 ‐ 32 ]. Of these patients, 40 (61.5%) had previously undergone microscopic surgery, while 25 (38.5%) had undergone prior endoscopic procedures. Importantly, a notable difference emerged between patients with residual disease and those experiencing recurrence regarding the prior surgical approach, with residual disease being less frequent after endoscopic surgery compared to microscopic surgery ( p  < 0.001). This variance was expected, as numerous studies have indicated that ETS yields a higher rate of complete resection compared to MTS [ 12 ‐ 14 ].
After the first repeat ETS, 47 patients (83.9%) achieved remission, and 78.5% ( n  = 44) of them maintained remission at a mean follow-up of 97.2 months without requiring additional surgery. Limited data exists regarding the remission rates of CD following repeat transsphenoidal surgery, with reported rates ranging from 28.9 to 73% [ 33 , 34 , 35 ]. Burke et al. reported an immediate remission rate of 86.7% and a continued remission rate of 73.3% at follow-up after repeat ETS [ 36 ]. Among our patients who achieved remission after successful repeat ETS, 3 individuals (6.38%, n  = 3/47) experienced recurrence after the first repeat ETS, with a mean time to recurrence of 45.6 months. The rates of CD recurrence following reoperation vary, with documented rates ranging between 22% and 63.2% [ 37 , 38 ]. In our study, 9 patients required a second repeat ETS due to residual disease or recurrence. Of these, 4 (44.4%) achieved continued remission following the second repeat ETS, while 5 (55.6%) had residual disease; however, 4 of them deferred further treatment, and 1 achieved remission after adrenalectomy. In total, 47 patients (83.9%) in the entire patient cohort achieved remission following endoscopic transsphenoidal surgery and did not require further intervention.
Within our case cohort, among the 42 patients who underwent repeat ETS for residual disease, 9 individuals (21.4%) continued to exhibit residual disease following the first repeat ETS. We did not establish a significant association between the success of repeat ETS and factors such as extension or invasion into cavernous sinuses, sellar or parasellar extension, or tumor size.
The degree of hypocortisolism following transsphenoidal surgery is considered a potential indicator of remission in the postoperative period [ 3 ]. Numerous studies have indicated that patients with subnormal postoperative cortisol levels tend to experience a lower recurrence rate compared to those with normal or supranormal levels, although consensus on the precise cutoff level remains elusive [ 30 ‐ 32 , 39 ]. In a retrospective study involving 52 patients with CD, researchers reported a 100% positive predictive value of a postoperative nadir cortisol level < 2 µg/dL for achieving remission [ 5 ]. Additionally, Esposito et al. observed that a morning serum cortisol level ≤ 5 µg/dL on postoperative day 1 or 2 appears to serve as a reliable predictor of remission [ 11 ]. In our investigation, logistic regression analysis revealed that patients with a serum cortisol level > 5 µg/dL on postoperative day 1 were less inclined to achieve continued remission compared to those with a serum cortisol level < 5 µg/dL on postoperative day 1.
Repeat transsphenoidal surgery presents unique challenges due to distorted surgical landmarks and the presence of scar tissue from prior procedures, often resulting in lower cure rates and increased morbidity risk [ 24 , 25 , 28 ]. Non-surgical options such as radiotherapy and radiosurgery have been considered as an effective treatment option for recurrent or residual CD due to low rates of morbidity and acceptable remission rates [ 28 , 40 ]. However, our findings suggest that the outcomes and complication rates associated with repeat ETS are comparable to primary ETS for CD and superior to other non-surgical options for residual or recurrent CD. Within our patient cohort, 5 (7.6%) individuals experienced transient diabetes insipidus (DI), while 2 (3%) developed permanent DI. Additionally, one patient (1.5%) experienced panhypopituitarism following the second repeat ETS. Similarly, various studies have reported DI rates ranging from 2 to 13% and panhypopituitarism rates between 2% and 9.7% [ 25 , 28 , 41 ‐ 43 ]. In our series, 3 (5.3%) patients developed rhinorrhea and required reoperation, consistent with reported rates of postoperative CSF leak ranging from 1 to 5% following repeat endoscopic transsphenoidal surgery for residual or recurrent pituitary tumors [ 25 , 28 , 44 ]. While radiotherapy and radiosurgery are options for patients who have failed transsphenoidal surgery or experienced recurrence, the literature suggests remission rates ranging from 46 to 84%, with several studies indicating high recurrence rates (25-50%) following radiotherapy [ 40 , 45 ‐ 47 ]. In our study, among 56 patients, 47 (83.9%) achieved remission following the first repeat ETS, while 4 (17.8%) achieved remission after the second repeat ETS. Over a mean follow-up duration of 97.25 months, our recurrence rate following repeat ETS was 27.7%, with a mean time to recurrence of 45.62 months.
At our institution, we adhere to a specific algorithm (Fig.  3 ) for managing Cushing’s disease patients and implement a meticulous protocol for individuals undergoing repeat ETS for residual or recurrent CD. A thorough clinical and radiological assessment is conducted for all patients before surgery. Detailed radiological evaluation is particularly essential to identify any distortions in surgical landmarks from prior procedures, such as the course of sphenoidal septa and the location of the sellar floor opening, as well as other potential aberrations like internal carotid artery and optic nerve dehiscence. Imaging techniques should encompass dynamic pituitary MRI with and without contrast and paranasal CT scans. Our objective is to achieve extensive exposure during surgery, which is especially critical for managing bifocal adenomas or adenomas with cavernous sinus invasion or extension. The expanded visual field also facilitates the visualization of concealed parts of the adenoma, allowing the surgeon to achieve complete resection, which may be challenging or even impossible with limited exposure. We employ a multilayer closure technique to prevent CSF leaks, and if necessary, utilize a vascularized pedicled nasoseptal flap (Hadad-Bassagasteguy flap).

https://static-content.springer.com/image/art%3A10.1007%2Fs11102-024-01396-x/MediaObjects/11102_2024_1396_Fig3_HTML.png

Fig. 3

Specific algorithm for the management of Cushing’s disease patients
In summary, our findings suggest that in the hands of experienced surgeons, repeat ETS represents a safe and effective treatment option for managing residual or recurrent Cushing’s disease.

Strengths and limitations

Our study represents one of the largest case series in the literature examining the safety, feasibility, and efficacy of repeat ETS for managing recurrent or residual CD. Our findings underscore the safety and efficacy of repeat ETS in experienced centers, showcasing satisfactory remission rates and minimal complications. However, it is important to acknowledge the retrospective nature of our study, which inherently introduces potential biases such as selection bias. Lastly, our study exclusively focuses on patients undergoing surgical intervention for recurrent or residual CD, limiting our ability to compare the effectiveness of surgical treatment with alternative modalities like radiotherapy or radiosurgery.

Conclusion

Our study underscores the efficacy and safety of repeat endoscopic transsphenoidal surgery in managing residual or recurrent Cushing’s disease. Remarkably, 82.1% of patients achieved remission after their first reoperation, aligning closely with reported remission rates following primary endoscopic transsphenoidal surgery. Furthermore, the complication rates observed in our cohort were consistent with documented rates for both primary and repeat transsphenoidal surgeries. Notably, patients with serum cortisol levels < 5 µg/dL are more likely to maintain remission. Overall, our findings emphasize that in the hands of experienced surgeons, repeat endoscopic transsphenoidal surgery emerges as a reliable and safe treatment modality for residual or recurrent Cushing’s disease, offering satisfactory remission rates and minimal complications.

Acknowledgments

Not applicable.

Declarations

Ethical approval

This study is approved by the ethics committee of the hospital where the research was conducted and informed consent is obtained from patients.

Competing interests

The authors declare no competing interests.
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Day 27, Cushing’s Awareness Challenge

Posted on April 27, 2024 by MaryO

I first saw a similar image to this one with the saying Life. Be in it at a recreation center when my son was little.  At the time, it was “Duh, of course, I’m in it”.

The original image was a couple of males, a couple of females, and a dog walking/running.  No folks in wheelchairs, no older folks, and certainly no zebras.

It would be nice to have everyone out there walking or running but that’s not real life, at least in the Cushie world.  It’s been a long time since I’ve really been In My Life – maybe it’s time to get back.

A dear friend who had not one, but two forms of cancer was traveling throughout Europe for the first time after her husband’s death wrote:

Some final words before I turn in for the night. If there is a spark of desire within you to do something which is not contrary to God’s Holy Law, find a way to make it happen. All things are possible and blessings abound for those who love Him. Life is such an adventure. Don’t be a spectator – live every single moment for Him and with Him.

Somedays, it’s hard even getting up in the morning but I’m trying.  Pre-COVID I took Water Aerobics for People with Arthritis and I actually went to class three times a week.

After COVID, I took the stuff I learned there and did it 3 times a week as part of “water walking” by myself or with my DH.   I got a “part-time” job several years ago and I’m  teaching piano online.  We had plans for a cruise to Norway which COVID made us reschedule for Alaska, which wass to be rescheduled…again.

I’ve recently started playing the balalaika with an orchestra even though I never even touched one before.

This is the one and only life I’ll ever have and I want to make the most of it!

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Day 26, Cushing’s Awareness Challenge

Posted on April 26, 2024 by MaryO

So often during the diagnosis phase of Cushing’s I felt lost like this picture – I was walking alone to an unknown place with an unknown future.

My diagnosis was pre-Internet which meant that any information had to be gotten from libraries, bookstores, magazines…or doctors.  In 1983 to 1986 I knew something was terribly wrong but there was no backup from doctors, family or friends.  My first hope was from a magazine (see Day Six)

After I got that first glimmer of hope, it was off to the library to try to understand medical texts.  I would pick out words I did understand – and it was more words each trip.  I made Xerox copies of my findings to read at home and try to digest. (I still have all those old pages!)

All my research led me to Cushing’s.

Unfortunately, the research didn’t lead me to doctors who could help for several years.  That contributed greatly to the loneliness.  If a doctor says you’re not sick, friends and family are going to believe the doctor, not you.  After all, he’s the one trained to know what’s wrong or find out.

I was so grateful when I finally got into a clinical trial at NIH and was so nice not to be alone with this mystery illness.  I was also surprised to learn, awful as I felt, there were Cushies much worse off than I was.

I am so glad that the Internet is here now helping us all know that we’re not alone anymore.

We’re all in this together with help, support, research, just being there.  I love this quote from Catherine at http://wheniwasyou.wordpress.com/2012/03/31/wheniwasyou/

Mary, I am delighted to see you here. Cushings – because of the persistent central obesity caused by (we know now) the lack of growth hormone plus the hypothyroidism I was diagnosed with (but for which treatment was ineffective due to my lack of cortisol) – was one of the things I considered as an explanation for my symptoms. Your site was enormously educational and helpful to me in figuring out what might be happening to me. Those other patient testimonies I referred to? Many of them were the bios you posted. Thank you so much for commenting. I am so grateful for the support and encouragement. I really hope that my experiences will help other undiagnosed hypopituitary patients find their way to a diagnosis. I often used to dream that one day I’d get to say to others what was so often said to me: don’t give up, there will be an answer. I kept believing in myself because people I hadn’t even met believed in me. Now I am finally here and I do hope my story will help others to have faith in their own instincts.

Thanks again. Please do keep in touch.

Catherine

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Unveiling the Uncommon: Cushing’s Syndrome (CS) Masquerading as Severe Hypokalemia

Posted on April 26, 2024 by MaryO

Abstract

Cushing’s syndrome (CS) arises from an excess of endogenous or exogenous cortisol, with Cushing’s disease specifically implicating a pituitary adenoma and exaggerated adrenocorticotropic hormone (ACTH) production. Typically, Cushing’s disease presents with characteristic symptoms such as weight gain, central obesity, moon face, and buffalo hump.

This case report presents an unusual manifestation of CS in a 48-year-old male with a history of hypertension, where severe hypokalemia was the primary presentation. Initial complaints included bilateral leg swelling, muscle weakness, occasional shortness of breath, and a general feeling of not feeling well. Subsequent investigations revealed hypokalemia, metabolic alkalosis, and an abnormal response to dexamethasone suppression, raising concerns about hypercortisolism. Further tests, including 24-hour urinary free cortisol and ACTH testing, confirmed significant elevations. Brain magnetic resonance imaging (MRI) identified a pituitary macroadenoma, necessitating neurosurgical intervention.

This case underscores the rarity of CS presenting with severe hypokalemia, highlighting the diagnostic challenges and the crucial role of a collaborative approach in managing such intricate cases.

Introduction

Cushing’s syndrome (CS), characterized by excessive cortisol production, is well-known for its diverse and often conspicuous clinical manifestations. Cushing’s disease is a subset of CS resulting from a pituitary adenoma overproducing adrenocorticotropic hormone (ACTH), leading to heightened cortisol secretion. The classic presentation involves a spectrum of symptoms such as weight gain, central obesity, muscle weakness, and mood alterations [1].

Despite its classic presentation, CS can demonstrate diverse and atypical features, challenging conventional diagnostic paradigms. This case report sheds light on a rare manifestation of CS, where severe hypokalemia was the primary clinical indicator. Notably, instances of CS prominently manifesting through severe hypokalemia are scarce in the literature [1,2].

Through this exploration, we aim to provide valuable insights into the diagnostic intricacies of atypical CS presentations, underscore the significance of a comprehensive workup, and emphasize the collaborative approach essential for managing such uncommon hormonal disorders.

Case Presentation

A 48-year-old male with a history of hypertension presented to his primary care physician with complaints of bilateral leg swelling, occasional shortness of breath, dizziness, and a general feeling of malaise persisting for 10 days. The patient reported increased water intake and urinary frequency without dysuria. The patient was diagnosed with hypertension eight months ago. He experienced progressive muscle weakness over two months, hindering his ability to perform daily activities, including using the bathroom. The primary care physician initiated a blood workup that revealed severe hypokalemia with a potassium level of 1.3 mmol/L (reference range: 3.6 to 5.2 mmol/L), prompting referral to the hospital.

Upon admission, the patient was hypertensive with a blood pressure of 180/103 mmHg, a heart rate of 71 beats/minute, a respiratory rate of 18 breaths/minute, and an oxygen saturation of 96% on room air. Physical examination revealed fine tremors, bilateral 2+ pitting edema in the lower extremities up to mid-shin, abdominal distension with normal bowel sounds, and bilateral reduced air entry in the bases of the lungs on auscultation. The blood work showed the following findings (Table 1).

Parameter Result Reference Range
Potassium (K) 1.8 mmol/L 3.5-5.0 mmol/L
Sodium (Na) 144 mmol/L 135-145 mmol/L
Magnesium (Mg) 1.3 mg/dL 1.7-2.2 mg/dL
Hemoglobin (Hb) 15.5 g/dL 13.8-17.2 g/dL
White blood cell count (WBC) 13,000 x 103/µL 4.5 to 11.0 × 109/L
Platelets 131,000 x 109/L 150-450 x 109/L
pH 7.57 7.35-7.45
Bicarbonate (HCO3) 46 mmol/L 22-26 mmol/L
Lactic acid 4.2 mmol/L 0.5-2.0 mmol/L
Table 1: Blood work findings

In order to correct the electrolyte imbalances, the patient received intravenous (IV) magnesium and potassium replacement and was later transitioned to oral. The patient was also started on normal saline at 100 cc per hour. To further investigate the complaint of shortness of breath, the patient underwent a chest X-ray, which revealed bilateral multilobar pneumonia (Figure 1). He was subsequently treated with ceftriaxone (1 g IV daily) and clarithromycin (500 mg twice daily) for seven days.

A-chest-X-ray-revealing-(arrows)-bilateral-multilobar-pneumonia
Figure 1: A chest X-ray revealing (arrows) bilateral multilobar pneumonia

With persistent abdominal pain and lactic acidosis, a computed tomography (CT) scan abdomen and pelvis with contrast was conducted, revealing a psoas muscle hematoma. Subsequent magnetic resonance imaging (MRI) depicted an 8×8 cm hematoma involving the left psoas and iliacus muscles. The interventional radiologist performed drainage of the hematoma involving the left psoas and iliacus muscles (Figure 2).

Magnetic-resonance-imaging-(MRI)-depicting-an-8x8-cm-hematoma-(arrow)-involving-the-left-psoas-and-iliacus-muscles
Figure 2: Magnetic resonance imaging (MRI) depicting an 8×8 cm hematoma (arrow) involving the left psoas and iliacus muscles

In light of the concurrent presence of hypokalemia, hypertension, and metabolic alkalosis, there arose concerns about Conn’s syndrome, prompting consultation with endocrinology. Their recommended workup for Conn’s syndrome included assessments of the aldosterone-renin ratio and random cortisol levels. The results unveiled an aldosterone level below 60 pmol/L (reference range: 190 to 830 pmol/L in SI units) and a plasma renin level of 0.2 pmol/L (reference range: 0.7 to 3.3 mcg/L/hr in SI units). Notably, the aldosterone-renin ratio was low, conclusively ruling out Conn’s syndrome. The random cortisol level was notably elevated at 1334 nmol/L (reference range: 140 to 690 nmol/L).

Furthermore, a low-dose dexamethasone suppression test was undertaken due to the high cortisol levels. Following the administration of 1 mg of dexamethasone at 10 p.m., cortisol levels were measured at 9 p.m., 3 a.m., and 9 a.m. the following day. The results unveiled a persistently elevated cortisol level surpassing 1655 nmol/L, signaling an abnormal response to dexamethasone suppression and raising concerns about a hypercortisolism disorder, such as CS.

In the intricate progression of this case, the investigation delved deeper with a 24-hour urinary free cortisol level, revealing a significant elevation at 521 mcg/day (reference range: 10 to 55 mcg/day). Subsequent testing of ACTH portrayed a markedly elevated level of 445 ng/L, distinctly exceeding the normal reference range of 7.2 to 63.3 ng/L. A high-dose 8 mg dexamethasone test was performed to ascertain the source of excess ACTH production. The baseline serum cortisol levels before the high-dose dexamethasone suppression test were 1404 nmol/L, which decreased to 612 nmol/L afterward, strongly suggesting the source of excess ACTH production to be in the pituitary gland.

A CT scan of the adrenal glands ruled out adrenal mass, while an MRI of the brain uncovered a 1.3×1.3×3.2 cm pituitary macroadenoma (Figure 3), leading to compression of adjacent structures. Neurosurgery was consulted, and they recommended surgical removal of the macroadenoma due to the tumor size and potential complications. The patient was referred to a tertiary care hospital for pituitary adenoma removal.

Magnetic-resonance-imaging-(MRI)-of-the-brain-depicting-a-1.3x1.3x3.2-cm-pituitary-macroadenoma-(star)
Figure 3: Magnetic resonance imaging (MRI) of the brain depicting a 1.3×1.3×3.2 cm pituitary macroadenoma (star)

Discussion

CS represents a complex endocrine disorder characterized by excessive cortisol production. While the classic presentation of CS includes weight gain, central obesity, and muscle weakness, our case highlights an uncommon initial manifestation: severe hypokalemia. This atypical presentation underscores the diverse clinical spectrum of CS and the challenges it poses in diagnosis and management [1,2].

While CS typically presents with the classic symptoms mentioned above, severe hypokalemia as the initial manifestation is exceedingly rare. Hypokalemia in CS often results from excess cortisol-mediated activation of mineralocorticoid receptors, leading to increased urinary potassium excretion and renal potassium wasting. Additionally, metabolic alkalosis secondary to cortisol excess further exacerbates hypokalemia [3,4].

Diagnosing a case of Cushing’s disease typically commences with a thorough examination of the patient’s medical history and a comprehensive physical assessment aimed at identifying characteristic manifestations such as central obesity, facial rounding, proximal muscle weakness, and increased susceptibility to bruising. Essential to confirming the diagnosis are laboratory examinations, which involve measuring cortisol levels through various tests, including 24-hour urinary free cortisol testing, late-night salivary cortisol testing, and dexamethasone suppression tests. Furthermore, assessing plasma ACTH levels aids in distinguishing between pituitary-dependent and non-pituitary causes of CS. Integral to the diagnostic process are imaging modalities such as MRI of the pituitary gland, which facilitate the visualization of adenomas and the determination of their size and precise location [1-4].

Treatment for Cushing’s disease primarily entails surgical removal of the pituitary adenoma via transsphenoidal surgery, with the aim of excising the tumor and restoring normal pituitary function. In cases where surgical intervention is unsuitable or unsuccessful, pharmacological therapies employing medications such as cabergoline (a dopamine receptor agonist) or pasireotide (a somatostatin analogue) may be considered to suppress ACTH secretion and regulate cortisol levels. Additionally, radiation therapy, whether conventional or stereotactic radiosurgery, serves as a supplementary or alternative treatment approach to reduce tumor dimensions and mitigate ACTH production [5,6]. To assess the effectiveness of treatment, manage any problem, and assure long-term illness remission, diligent long-term follow-up and monitoring are essential. Collaborative multidisciplinary care involving specialists such as endocrinologists, neurosurgeons, and other healthcare professionals is pivotal in optimizing patient outcomes and enhancing overall quality of life [2,4].

The prognosis of CS largely depends on the underlying cause, stage of the disease, and efficacy of treatment. Early recognition and prompt intervention are essential for improving outcomes and minimizing long-term complications. Surgical resection of the adrenal or pituitary tumor can lead to remission of CS in the majority of cases. However, recurrence rates vary depending on factors such as tumor size, invasiveness, and completeness of resection [2,3]. Long-term follow-up with endocrinologists is crucial for monitoring disease recurrence, assessing hormonal function, and managing comorbidities associated with CS.

Conclusions

In conclusion, our case report highlights the rarity of severe hypokalemia as the initial presentation of CS. This unique presentation underscores the diverse clinical manifestations of CS and emphasizes the diagnostic challenges encountered in clinical practice. A multidisciplinary approach involving endocrinologists, neurosurgeons, and radiologists is essential for the timely diagnosis and management of CS. Early recognition, prompt intervention, and long-term follow-up are essential for optimizing outcomes and improving the quality of life for patients with this endocrine disorder.

References

  1. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93:1526-40. 10.1210/jc.2008-0125
  2. Newell-Price J, Bertagna X, Grossman AB, Nieman LK: Cushing’s syndrome. Lancet. 2006, 367:1605-17. 10.1016/S0140-6736(06)68699-6
  3. Torpy DJ, Mullen N, Ilias I, Nieman LK: Association of hypertension and hypokalemia with Cushing’s syndrome caused by ectopic ACTH secretion: a series of 58 cases. Ann N Y Acad Sci. 2002, 970:134-44. 10.1111/j.1749-6632.2002.tb04419.x
  4. Elias C, Oliveira D, Silva MM, Lourenço P: Cushing’s syndrome behind hypokalemia and severe infection: a case report. Cureus. 2022, 14:e32486. 10.7759/cureus.32486
  5. Fleseriu M, Petersenn S: Medical therapy for Cushing’s disease: adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers. Pituitary. 2015, 18:245-52. 10.1007/s11102-014-0627-0
  6. Pivonello R, De Leo M, Cozzolino A, Colao A: The treatment of Cushing’s disease. Endocr Rev. 2015, 36:385-486. 10.1210/er.2013-1048

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Day 24: Cushing’s Awareness Challenge

Posted on April 24, 2024 by MaryO

Over the years, we went on several Windjammer Barefoot Cruises.  We liked them because they were small, casual and were fairly easy on the wallet.

They sailed around the Caribbean to a variety of islands, although they sometimes changed itineraries depending on weather, crew, whatever.  One trip we were supposed to go to Saba but couldn’t make port.  A lot of people got off at the next port and flew home.

The captains were prone to “Bedtime Stories” which were often more fiction than true but they added to the appeal of the trip.  We didn’t care if we missed islands or not – we were just there to sail over the waves and enjoy the ride.

The last trip we took with them was about two years before I started having Cushing’s problems.  (You wondered how I was going to tie this together, right?)

The cruise was uneventful, other than the usual mishaps like hitting docks, missing islands and so on.  Until it was a particularly rough sea one day.  I was walking somewhere on deck and suddenly a wave came up over the deck making it very slippery.  I fell and cracked the back of my head on the curved edge of a table in the dining area.  I had the next-to-the-worse headache I have ever had, the worst being after my pituitary surgery. At least after the surgery, I got some morphine.

We asked several doctors later if that hit could have contributed to my Cushing’s but doctors didn’t want to get involved in that at all.

The Windjammer folks didn’t fare much better, either. In October 1998, Hurricane Mitch was responsible for the loss of the s/v Fantome (the last one we were on). All 31 crew members aboard perished; passengers and other crew members had earlier been offloaded in Belize.

 

The story was recorded in the book The Ship and the Storm: Hurricane Mitch and the Loss of the Fantome by Jim Carrier.  The ship, which was sailing in the center of the hurricane, experienced up to 50-foot (15 m) waves and over 100 mph (160 km/h) winds, causing the Fantome to founder off the coast of Honduras.

“In October 1998, the majestic schooner Fantome came face-to-face with one of the most savage storms in Atlantic history. The last days of the Fantome are reconstructed in vivid and heartbreaking detail through Jim Carrier’s extensive research and hundreds of personal interviews. What emerges is a story of courage, hubris, the agony of command, the weight of lives versus wealth, and the advances of science versus the terrible power and unpredictability of nature.”

This event was similar to the Perfect Storm in that the weather people were more interested in watching the hurricane change directions than they were in people who were dealing with its effects.

I read this book and I was really moved by the plight of those crew members.

I’ll never know if that hit on my head contributed to my Cushing’s but I have seen several people mention on the message boards that they had a traumatic head injury of some type in their earlier lives.

 

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