Related Factors of Delirium After Transsphenoidal Endoscopic Pituitary Adenoma Resection

Posted on April 11, 2024 by MaryO

Highlights

  • Aim to identify independent risk factors for postoperative delirium after pituitary adenoma surgery.
  • Select matched subjects by Propensity Score Matching to reduce potential biases caused by variables.
  • Enhance preoperative communication to minimize the occurrence of delirium, for patients at high risk of postoperative delirium.
  • Minimize surgery duration and general anesthesia, optimize perioperative sedation regimen.
  • Reducing unnecessary or excessive protective physical restraints.

Abstract

Objectives

The primary aim of this study is to explore the factors associated with delirium incidence in postoperative patients who have undergone endoscopic transsphenoidal approach surgery for pituitary adenoma.

Methods

The study population included patients admitted to Tianjin Huanhu Hospital’s Skull Base Endoscopy Center from January to December 2022, selected through a retrospective cohort study design. The presence of perioperative delirium was evaluated using the 4 ‘A’s Test (4AT) scale, and the final diagnosis of delirium was determined by clinicians. Statistical analysis included Propensity Score Matching (PSM), χ2 Test, and Binary Logistic Regression.

Results

A total of 213 patients were included in this study, and the incidence of delirium was found to be 29.58 % (63/213). Among them, 126 patients were selected using PSM (delirium:non-delirium = 1:1), ensuring age, gender, and pathology were matched. According to the results of univariate analysis conducted on multiple variables, The binary logistic regression indicated that a history of alcoholism (OR = 6.89, [1.60–29.68], P = 0.010), preoperative optic nerve compression symptoms (OR = 4.30, [1.46–12.65], P = 0.008), operation time ≥3 h (OR = 5.50, [2.01–15.06], P = 0.001), benzodiazepines for sedation (OR = 3.94, [1.40–11.13], P = 0.010), sleep disorder (OR = 3.86, [1.40–10.66], P = 0.009), and physical restraint (OR = 4.53, [1.64–12.53], P = 0.004) as independent risk factors for postoperative delirium following pituitary adenoma surgery.

Conclusions

For pituitary adenoma patients with a history of alcoholism and presenting symptoms of optic nerve compression, as well as an operation time ≥3 h, enhancing communication between healthcare providers and patients, improving perioperative sleep quality, and reducing physical restraint may help decrease the incidence of postoperative delirium.

Introduction

In clinical practice, patients admitted to the intensive care unit (ICU) during the postoperative period after endoscopic transsphenoidal tumorectomy of pituitary adenoma often experience episodes of delirium. According to a recent retrospective analysis conducted at a single center, the incidence of postoperative delirium among these patients was found to be 10.34 % (n = 360) [1]. Delirium is a common complication following neurosurgery, characterized by acute distraction, confusion in thinking, sleep disorders, and cognitive decline. The incidence of delirium in admitted patients after neurosurgery has been reported to be 19 %, with a range of 12 % to 26 % depending on clinical features and the methods used for delirium assessment [2], [3], [4]. The incidence of postoperative delirium varied across different types of neurosurgical diseases, as reported in a meta-analysis [2]. Specifically, the incidences were 8.0 % for patients with neurological tumors, 20 % for those undergoing functional neurosurgery, 24.0 % for microvascular decompression patients, 19.0 % for traumatic brain injury patients, 42.0 % for neurovascular patients, and 17.0 % for the mixed population undergoing neurosurgery procedures. Furthermore, the incidence rates of delirium in intensive care units (ICUs), general wards, or both combined were found to be 24.0 %, 17 %, and 18 %, respectively.

The aforementioned issue not only leads to prolonged hospital stays and increased healthcare costs, but also exerts a significant impact on patient consciousness and cognitive function. Therefore, early and accurate identification of delirium in post-neurosurgical patients is crucial. However, due to frequent co-occurrence with primary brain injury, related complications can also lead to cognitive impairment or even decreased levels of consciousness, posing challenges for timely and precise identification of delirium. Currently, the primary focus lies in the prevention of delirium within the neurosurgical ICU setting. Early identification and comprehensive pre-surgical assessment are positively significant measures for preventing postoperative delirium occurrence [5], [6]. In this study, a retrospective cohort design was employed to collect pertinent data and statistically analyze the incidence of delirium, as well as its associated influencing factors, among patients admitted to the neurosurgical ICU for pituitary adenoma treatment. And now it is reported as follows.

Section snippets

Patient selection

A retrospective cohort study design was employed to select 213 pituitary adenomas admitted to the Skull Base and Endoscopy Center of Tianjin Huanhu Hospital between January 2022 and December 2022 as the subjects for investigation, with a review of their medical records. The mean age was (50.03 ± 15.72) years, ranging from 20–79 years old (Fig. 1). Informed consent was obtained from all patients or their families, ensuring compliance with the requirements stated in the Declaration of Helsinki.

Inclusion criteria

a.

Propensity score matching

The present study enrolled a total of 213 patients with pituitary tumors, among whom 63 exhibited symptoms related to delirium while the remaining 150 did not. Consequently, the incidence rate of delirium was determined to be 29.58 % in this cohort of patients admitted to the intensive care unit following pituitary tumor surgery. The univariate analysis revealed no significant differences in age (≥65y old, 23.8 % vs. 23.3 %, P = 0.940) and gender (male, 49.2 % vs. 56.7 %, P = 0.318) between the

Background of perioperative delirium in transsphenoidal endoscopic pituitary adenoma surgery

The pituitary gland is situated within the sella turcica and comprises two distinct components. The anterior pituitary, known as the adenohypophysis, functions as an endocrine organ responsible for secreting growth hormone, prolactin, adrenocorticotropic hormone, thyrotropin, follicle-stimulating hormone and luteinizing hormone. On the other hand, the posterior pituitary, referred to as the neurohypophysis, serves as a direct extension of the hypothalamus and acts as a storage site for

Conclusions

To enhance the evaluation of postoperative patients at risk of delirium, it is anticipated that optimizing doctor-nurse-patient communication and minimizing unnecessary and indiscriminate protective measures will mitigate the incidence of delirium following pituitary tumor surgery. This study is a single-center prospective study conducted at our institution, which has several inherent limitations. A large-scale multicenter prospective study is anticipated to further investigate the associated

Limitations

There are multiple factors that influence the occurrence of delirium following neurosurgery. This retrospective study solely focused on analyzing and comparing general patient data, medical history, and potential perioperative factors contributing to delirium, without considering any other known or unknown variables in this analysis. The pituitary gland functions as a neuroendocrine organ involved in the regulation of neuroendocrine processes. Changes in hormone levels following surgery for

Funding

All authors affirm that this study was conducted without any fund support from external organizations.

CRediT authorship contribution statement

Shusheng Zhang: Writing – original draft, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Yanan Chen: Writing – original draft, Investigation, Data curation. Xiudong Wang: Validation, Supervision, Project administration, Methodology, Conceptualization. Jun Liu: Software, Formal analysis, Data curation. Yueda Chen: Validation, Supervision, Methodology, Investigation. Guobin Zhang: Writing – review & editing, Validation, Supervision, Methodology, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References (21)

There are more references available in the full text version of this article.

Filed under: Cushing's, pituitary, Treatments | Tagged: , , , | Leave a comment »

Talus Avascular Necrosis as a Rare Complication of Cushing’s Disease

Posted on April 8, 2024 by MaryO

Abstract

Avascular necrosis (AVN), also called osteonecrosis, stems from blood supply interruption to the bone and is often idiopathic. It has risk factors like trauma, alcohol, and corticosteroids. AVN in the talus (AVNT) is less common than in the femoral head. Most cases of talar osteonecrosis are associated with trauma, while a smaller proportion is linked to systemic conditions such as sickle cell disease or prolonged prednisone use. Glucocorticoids are a key nontraumatic cause. We report a middle-aged woman with Cushing’s syndrome symptoms, such as hypertension and moon face, since her youth. A few years ago, she experienced pain and swelling in her ankle, which was diagnosed as atraumatic AVNT and treated with hindfoot fusion. Years later, she was diagnosed with Cushing’s disease caused by an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma in laboratory tests and imaging, which was resected in 2020. She experienced significant weight loss, and her Cushing’s syndrome symptoms were relieved after tumor resection. Mechanisms behind AVN in hypercortisolism involve fat cell hypertrophy, fat embolization, osteocyte apoptosis, and glucocorticoid-induced hypertension. Traditional X-rays may miss early AVN changes; MRI is preferred for early detection. Although there are some cases of femoral AVN caused by endogenous hypercortisolism in the literature, as far as we know, this is the first case of AVNT due to Cushing’s disease. AVNT treatment includes conservative approaches, hindfoot fusion, and core decompression. Cushing’s disease is a rare cause of AVNT, and a multidisciplinary approach aids in the rapid diagnosis of elusive symptoms.

Introduction

Avascular necrosis (AVN), also known as osteonecrosis, is a condition arising from the temporary interruption or permanent cessation of blood supply to a bone, leading to tissue necrosis or its demise. While AVN is frequently idiopathic, certain established risk factors are known including trauma, alcohol abuse, and the use of exogenous corticosteroids [1]. While not as prevalent as in the femoral head, AVN of the talus (AVNT) in the ankle presents a painful and disabling issue for patients and poses a challenging dilemma for orthopedic surgeons [2]. About 75% of cases of talar osteonecrosis stem from traumatic injuries, while approximately 25% of nontraumatic instances are typically associated with systemic conditions such as sickle cell disease or prolonged use of prednisone, which impede blood flow. [3]

The use of glucocorticoids is one of the most important non-traumatic causes of AVN. Nevertheless, there are some case reports where AVN in the femoral head is reported as a manifestation of endogenous hypercortisolism, particularly associated with Cushing’s syndrome [4-12].

In this article, we describe the case of a middle-aged woman who was diagnosed with idiopathic severe progressive AVNT for two years. She had retrogradely diagnosed masked symptoms of Cushing’s disease since her youth, but the diagnosis was confirmed after undergoing ankle arthrodesis.

Case Presentation

A 43-year-old woman visited our office in June 2018 with a complaint of severe pain and swelling in her left ankle, which had persisted for the past two years. She had hypertension since her youth and blurry vision since 2013 but had no other significant medical or family history. She was also diagnosed with major depressive disorder (MDD) in 2015 when she lost her husband. She had no history of smoking, alcohol consumption, or addiction. She had not experienced any significant trauma during this period and sought consultations from various specialties, including neurology, psychology, internal medicine, nephrology, rheumatology, and orthopedics. She had received a platelet-rich plasma (PRP) injection in the ankle, but it did not improve her symptoms. Despite undergoing various diagnostic workups, no precise diagnosis had been established.

Back in 2013, she remembers suddenly experiencing blurry vision in her right eye. This condition underwent a misdiagnosis, which almost led to a loss of vision. She had been struggling with her eye problems until her last visit, during which she received intravitreal bevacizumab injections. Additionally, she previously had iron deficiency anemia, which was treated with ferrous sulfate before 2018.

In our first visit, during the physical examination, the pain was localized in the ankle mortise with some posterolateral pain along the course of the peroneal tendons posterior to the fibula. Based on the physical examination and available ankle radiographs, we diagnosed AVNT. The patient subsequently underwent ankle arthroscopy through the standard anterior portals, the joint was cleaned, the synovium was shaved, and a small incision was conducted for peroneal assessment; this procedure revealed a subchondral collapse and extensive necrosis in the talus. Following the procedure, she experienced a partial improvement in her symptoms. However, six months later, she returned with a recurrence of symptoms (Figure 1). Upon further inquiry, she mentioned that her symptoms had recurred a month ago when she was dancing at a family party. Radiographs showed a stress fracture in her fibula and extensive AVNT. This diagnosis was confirmed through a CT scan, MRI, and bone scan (Figure 2).

Ankle-X-ray-six-months-after-arthroscopy
Figure 1: Ankle X-ray six months after arthroscopy

Pain had reduced for four months, then pain increased with activity and disabled her after a night of dancing. Subchondral fracture and fibular stress fracture are evident (A and B, respectively).

MRI,-CT-scan,-and-technetium-99m-(Tc-99m)-bone-scan
Figure 2: MRI, CT scan, and technetium-99m (Tc-99m) bone scan

Coronal MRI confirmed avascular necrosis of the talar dome with subchondral fracture (A and B, respectively). CT scan (C) and Tc-99 bone scan (D) images also revealed the pathologies.

In the second visit after arthroscopy, upon confirmation of a fibular stress fracture and significant subchondral collapse, and following a discussion of the next available options with the patient, the second procedure was performed as an ankle arthrodesis with an anterior approach. A 6 cm longitudinal incision was made anteriorly, and through the plane between the tibialis anterior and extensor hallucis longus, the ankle joint was accessed. Joint preparation was done with an osteotome, ensuring a bleeding surface on both sides. Then, manual compression with provisional pin fixation in the corrective position was performed. The fusion was planned at less than 5 degrees of valgus, 10 degrees of external rotation, and approximately 10 degrees of plantar flexion, suitable for the high-heeled shoes that she was using in her daily living activities. After confirming fluoroscopy in two planes, final 6.5 mm cannulated cancellous screws were used, and fixation was augmented with an anterior molded 4.5 mm narrow dynamic compression plate (DCP), according to our previously published anterior ankle fusion technique [13]. The foot was placed in a splint for 10 days, after which stitches were removed, and a cast was applied for four weeks. Then, walking with gradual, as-tolerated weight-bearing was initiated (Figure 3). Three months after surgery, she was pain-free, and by the sixth month, she could walk without any boot or brace, only using high-heeled shoes.

Post-operative-radiographies
Figure 3: Post-operative radiographies

Six months after the ankle surgery, a huge osteonecrosis and fibular stress fracture were managed with an acceptable, painless ankle fusion (not solid) despite the remaining necrosis (A and B, respectively). In 2024, four years after the tumor resection, complete healing of talus necrosis and solid fusion were achieved (C and D, respectively).

In 2020, two years after her ankle surgery, she was referred to an endocrinologist due to excessive weight gain and hirsutism. The biochemical assessment revealed the following: cortisol (8 AM) (chemiluminescence immunoassay (CLIA)) was 96 µg/dl (normal range: 4.82 – 19.5 µg/dl), and it was 22.1 µg/dl after overnight dexamethasone (normal range: < 1.8 µg/dl). Adrenocorticotropic hormone (ACTH) (CLIA) was 44.4 pg/ml (normal range: 7.2-63.3 pg/ml), and cortisol measured 5.7 µg/dl after the 48-hour low-dose dexamethasone suppression test (normal < 5 µg/dl). The results, along with symptoms (Table 1), are documented in the laboratory tests (Table 2). She was diagnosed with Cushing’s syndrome, which was subsequently confirmed as Cushing’s disease due to an ACTH-producing pituitary adenoma observed in the MRI and Brain CT (Figure 4).

Sign/symptom Severity
Weight Gain Severe
Hirsutism Severe
Hypertension Severe
Easy bruising Severe
Depression Severe
Moon face Moderate (masked with makeup)
Lethargy Moderate
Headache Moderate
Peripheral edema       _
Buffalo hump       _
Myopathy       _
Acne       _
Purple striae       _
Table 1: Cushing’s disease symptoms and signs

The hyphens in the table indicate that the patient does not have those symptoms or signs.

Laboratory test Result Reference range
Cortisol (8 AM) (CLIA) 96 µg/dl 4.82-19.5 µg/dl
Cortisol (8 AM) (after overnight dexamethasone) (CLIA) 22.1 µg/dl <1.8 µg/dl
ACTH (CLIA) 44.4 pg/ml 7.2-63.3 pg/ml
Cortisol after 48 hours of LDDST (CLIA) 5.7 µg/dl < 5 µg/dl
Table 2: Laboratory tests

CLIA: chemiluminescence immunoassay; ACTH: adrenocorticotropic hormone; LDDST: low-dose dexamethasone suppression test

Brain-MRI
Figure 4: Brain MRI

Finally, a pituitary adenoma was diagnosed using a Brain MRI as the cause of Cushing’s disease symptoms (A and B).

Finally, she underwent a tumor resection and had a dramatic response after treatment (30 kg weight loss). She revealed that she had Cushing’s syndrome symptoms since she was young. These symptoms included a puffy face, which she covered with makeup, high blood pressure, and hirsutism. In January 2024, four years after her brain surgery, during our last visit, her symptoms had significantly improved. She reported no problems with her ankle, and talus necrosis was completely healed, with a solid fusion achieved in radiographs (Figure 3).

Discussion

As far as we are aware, this case presentation represents the first instance of AVNT attributed to Cushing’s disease in the existing literature. Nevertheless, some individuals with endogenous Cushing’s syndrome have been reported to experience AVN of the femoral head [4-12].

Cushing’s syndrome is an uncommon endocrine condition marked by manifestations of hypercortisolism. The predominant cause is often an adenoma in the anterior pituitary gland that produces ACTH, referred to as Cushing’s disease [14]. The presentation of Cushing’s syndrome can vary significantly in both adults and children, influenced by the extent and duration of hypercortisolemia. However, the typical signs and symptoms of Cushing’s syndrome are widely known [15]. Although some individuals may perceive these alterations as normal and physiological, the disease can go unnoticed for an extended period, as in our case, in which it remained undiagnosed for more than 20 years.

However, it is known that steroid use is a significant contributing factor to the occurrence of bone osteonecrosis, accounting for up to 40% of non-traumatic instances of AVN [16]. The mechanisms leading to AVN due to either endogenous hypercortisolism or excess exogenous glucocorticoids are not completely understood. There are just some hypotheses that suggest that the hypertrophy of fat cells, embolization of fat, and osteocytes’ apoptosis result in impaired blood flow in the bone, ultimately causing ischemic tissue necrosis [17]. An alternative proposed theory suggests that elevated levels of glucocorticoids may cause insulin resistance and subsequently contribute to AVN [18].

Traditional X-rays often fail to detect the initial changes of AVN (as observed in our case). MRI stands as the preferred method for identifying AVN in its early phases, providing an opportunity for timely therapeutic interventions [19,20].

In an analysis of 321 cases of AVNT, the predominant treatment modalities included conservative therapies (n = 104), hindfoot fusion (n = 62), and core decompression (n = 85) [21]. These approaches reflect the primary methods employed in contemporary clinical practice for addressing AVNT.

After all, we confirmed the AVNT diagnosis using MRI and bone scan and managed it with hindfoot fusion. Subsequently, the underlying issue, endogenous hypercortisolism due to an ACTH-producing pituitary adenoma, was identified and treated through resection of the tumor (Figure 5).

Case-report-timeline
Figure 5: Case report timeline

* Avascular necrosis in the talus

Conclusions

Cushing’s syndrome is a rare endocrine disorder characterized by excessive cortisol levels, commonly caused by an ACTH-producing adenoma in the pituitary gland, known as Cushing’s disease. Cushing’s disease may be one of the rare causes of AVNT. To the best of our knowledge, this is the first instance of AVNT due to Cushing’s disease described in the literature. Since atraumatic AVNT is rare in itself, a multidisciplinary approach can lead us to a more rapid and proper diagnosis, as each symptom may be masked or considered rare within its subspecialty field.

References

  1. Chang CC, Greenspan A, Gershwin ME: Osteonecrosis: current perspectives on pathogenesis and treatment. Semin Arthritis Rheum. 1993, 23:47-69. 10.1016/s0049-0172(05)80026-5
  2. Zhang H, Fletcher AN, Scott DJ, Nunley J: Avascular osteonecrosis of the talus: current treatment strategies. Foot Ankle Int. 2022, 43:291-302. 10.1177/10711007211051013
  3. Parekh SG, Kadakia RJ: Avascular necrosis of the talus. J Am Acad Orthop Surg. 2021, 29:e267-78. 10.5435/JAAOS-D-20-00418
  4. Belmahi N, Boujraf S, Larwanou MM, El Ouahabi H: Avascular necrosis of the femoral head: an exceptional complication of Cushing’s disease. Ann Afr Med. 2018, 17:225-7. 10.4103/aam.aam_75_17
  5. Salazar D, Esteves C, Ferreira MJ, Pedro J, Pimenta T, Portugal R, Carvalho 😧 Avascular femoral necrosis as part of Cushing syndrome presentation: a case report. J Med Case Rep. 2021, 15:287. 10.1186/s13256-021-02882-7
  6. Alaya Z, Braham M, Bouajina E: Aseptic femur head necrosis revealing Cushing’s disease: a rare presentation. J Clin Surg Res. 2020, 1:10.31579/2768-2757/002
  7. Phillips KA, Nance EP Jr, Rodriguez RM, Kaye JJ: Avascular necrosis of bone: a manifestation of Cushing’s disease. South Med J. 1986, 79:825-9. 10.1097/00007611-198607000-00011
  8. Koch CA, Tsigos C, Patronas NJ, Papanicolaou DA: Cushing’s disease presenting with avascular necrosis of the hip: an orthopedic emergency. J Clin Endocrinol Metab. 1999, 84:3010-2. 10.1210/jcem.84.9.5992
  9. Modroño N, Torán CE, Pavón I, Benza ME, Guijarro G, Navea 😄 Cushinǵs syndrome and avascular hip necrosis: presentation of two patients [Article in Spanish]. Rev Clin Esp (Barc). 2014, 214:e93-6. 10.1016/j.rce.2014.05.003
  10. Camporro F, Bulacio E, Gutiérrez Magaldi I: Bilateral osteonecrosis of the hip secondary to endogenous Cushing’s syndrome due to a recently-diagnosed carcinoid tumour of the lung [Article in Spanish]. Med Clin (Barc). 2016, 147:228. 10.1016/j.medcli.2016.03.042
  11. Ha JS, Cho HM, Lee HJ, Kim SD: Bilateral avascular necrosis of the femoral head in a patient with asymptomatic adrenal incidentaloma. Hip Pelvis. 2019, 31:120-3. 10.5371/hp.2019.31.2.120
  12. Anand A, Jha CK, Singh PK, Sinha U, Ganesh A, Bhadani PP: Avascular necrosis of femur as a complication of Cushing’s syndrome due to adrenocortical carcinoma. Am Surg. 2023, 89:2701-4. 10.1177/00031348221129510
  13. Gharehdaghi M, Rahimi H, Mousavian A: Anterior ankle arthrodesis with molded plate: technique and outcomes. Arch Bone Jt Surg. 2014, 2:203-9.
  14. Lindholm J, Juul S, Jørgensen JO, et al.: Incidence and late prognosis of cushing’s syndrome: a population-based study. J Clin Endocrinol Metab. 2001, 86:117-23. 10.1210/jcem.86.1.7093
  15. 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
  16. Konarski W, Poboży T, Konarska K, Śliwczyński A, Kotela I, Hordowicz M, Krakowiak J: Osteonecrosis related to steroid and alcohol use-an update on pathogenesis. Healthcare (Basel). 2023, 11:1846. 10.3390/healthcare11131846
  17. Chan KL, Mok CC: Glucocorticoid-induced avascular bone necrosis: diagnosis and management. Open Orthop J. 2012, 6:449-57. 10.2174/1874325001206010449
  18. Hartmann K, Koenen M, Schauer S, Wittig-Blaich S, Ahmad M, Baschant U, Tuckermann JP: Molecular actions of glucocorticoids in cartilage and bone during health, disease, and steroid therapy. Physiol Rev. 2016, 96:409-47. 10.1152/physrev.00011.2015
  19. Kaste SC, Karimova EJ, Neel MD: Osteonecrosis in children after therapy for malignancy. AJR Am J Roentgenol. 2011, 196:1011-8. 10.2214/AJR.10.6073
  20. Pierce TP, Jauregui JJ, Cherian JJ, Elmallah RK, Mont MA: Imaging evaluation of patients with osteonecrosis of the femoral head. Curr Rev Musculoskelet Med. 2015, 8:221-7. 10.1007/s12178-015-9279-6
  21. Gross CE, Haughom B, Chahal J, Holmes GB Jr: Treatments for avascular necrosis of the talus: a systematic review. Foot Ankle Spec. 2014, 7:387-97. 10.1177/1938640014521831

From https://www.cureus.com/articles/221491-talus-avascular-necrosis-as-a-rare-complication-of-cushings-disease-a-case-report?score_article=true#!/

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Filed under: Cushing's, pituitary, Rare Diseases, symptoms | Tagged: , , | Leave a comment »

PET/MRI may improve diagnosis of Cushing disease

Posted on April 5, 2024 by MaryO

PET/MRI could become the diagnostic method of choice over MRI alone for identifying small pituitary tumors associated with Cushing disease, according to a study published March 21 in the Journal of Nuclear Medicine.

In patients diagnosed with the disease yet who had inconclusive MRI results, PET/MRI was positive in 100% of cases, noted lead author Ilanah Pruis, a doctoral student at Erasmus University Medical Center in Rotterdam, Netherlands.

“This multimodal imaging technique provides a welcome improvement for diagnosis, planning of surgery, and clinical outcome in patients with Cushing disease,” the authors wrote.

Cushing disease is characterized by small tumors in pituitary glands, which causes them to secrete excess cortisol, the authors explained. While it is a rare disease, over time it can cause severely disabling conditions, such as high blood pressure or type II diabetes.

Currently, guidelines recommend the use of MRI and inferior petrosal sinus sampling (IPSS) to diagnose these tumors. IPSS is an invasive procedure in which cortisol hormone levels are sampled from the veins that drain the pituitary gland.

In up to 40% of patients, however, MRI is inconclusive, as the lesions are smaller than 10 millimeters in diameter. Even advanced MRI techniques, such as dynamic perfusion imaging, can leave small lesions undetected in up to one third of patients, the authors noted.

In preclinical work, PET imaging using a radiotracer named F-18 FET has been shown to bind with high affinity to a molecular target in pituitary tumors, and in this study, the researchers aimed to test this technique combined with MRI in a multimodal approach.

The researchers analyzed results from 22 patients (68% women; mean age 48 years) who underwent F-18 FET PET/MRI at Erasmus MC between February 2021 and December 2022. All patients showed a clear pituitary tumor F-18 FET-PET/MRI, whereas reading of the MRI alone yielded a suspected lesion in only 50%, the authors found.

T1-weighted postgadolinium MR images (A and C) and F-18 FET-PET/MR images (B and D) centered at pituitary before (A and B) and after (C and D) transsphenoidal surgery. This patient with Cushing disease showed clear focal uptake (B) but no clear lesion on previously obtained and accompanying MRI (A). Postoperative tissue analysis did confirm resection of small pituitary adenoma/PitNET, and postoperative F-18 FET-PET showed no residual uptake (D). Image courtesy of the Journal of Nuclear Medicine.T1-weighted postgadolinium MR images (A and C) and F-18 FET-PET/MR images (B and D) centered at pituitary before (A and B) and after (C and D) transsphenoidal surgery. This patient with Cushing disease showed clear focal uptake (B) but no clear lesion on previously obtained and accompanying MRI (A). Postoperative tissue analysis did confirm resection of small pituitary adenoma/PitNET, and postoperative F-18 FET-PET showed no residual uptake (D). Image courtesy of the Journal of Nuclear Medicine.

Importantly, 16 patients underwent treatment based on the results — either surgery, Gamma Knife, or CyberKnife therapy — with 12 of these patients achieving short-term remission, the authors noted.

“[F-18 FET-PET/MRI] is of great clinical value because it allows precision surgery and targeted Gamma Knife or CyberKnife therapy,” the group wrote.

The researchers noted that only one previous study evaluated F-18 FET-PET/MRI in these patients and that their study was limited, given the relatively small number of patients.

“Future studies will be directed at head-to-head comparisons of the performance of F-18 FET- PET and other diagnostic techniques, including advanced MRI sequences… preferably in patients at the time of initial clinical presentation,” the authors concluded.

A link to the full study can be found here.

From https://www.auntminnie.com/clinical-news/molecular-imaging/article/15667496/petmri-may-improve-diagnosis-of-cushing-disease

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Corcept Completes Enrollment in Phase 3 Gradient Trial of Relacorilant in Patients With Adrenal Cushing’s Syndrome

Posted on April 3, 2024 by MaryO

Corcept Therapeutics Incorporated (NASDAQ: CORT), a commercial-stage company engaged in the discovery and development of medications to treat severe endocrinologic, oncologic, metabolic and neurologic disorders by modulating the effects of the hormone cortisol, today announced completion of enrollment in GRADIENT, a Phase 3 trial of its proprietary selective cortisol modulator relacorilant in patients with Cushing’s syndrome (hypercortisolism) caused by an adrenal adenoma or adrenal hyperplasia.

“Hypercortisolism with adrenal etiology affects many patients and is associated with serious cardiometabolic comorbidities, including hypertension and hyperglycemia, and increased risk of premature death,” said Bill Guyer, PharmD, Corcept’s Chief Development Officer. “GRADIENT is the first prospective placebo-controlled study to be conducted exclusively in these patients with Cushing’s syndrome. We expect data from GRADIENT in the fourth quarter of this year.”

GRADIENT is a randomized, double-blind, placebo-controlled trial conducted at sites in the United States, Europe and Israel. One-hundred thirty-seven patients were randomized 1:1 to receive relacorilant or placebo for 22 weeks. Primary endpoints are improvement in glucose metabolism and hypertension.

About Cushing’s Syndrome (Hypercortisolism)
Cushing’s syndrome is caused by excessive activity of the hormone cortisol. Endogenous Cushing’s syndrome is an orphan disease that most often affects adults aged 20-50. Symptoms vary, but most patients experience one or more of the following manifestations: high blood sugar, diabetes, high blood pressure, upper-body obesity, rounded face, increased fat around the neck, thinning arms and legs, severe fatigue and weak muscles. Irritability, anxiety, cognitive disturbances and depression are also common. Cushing’s syndrome can affect every organ system and can be lethal if not treated effectively.

About Relacorilant
Relacorilant is a selective cortisol modulator that binds to the glucocorticoid receptor (GR), but does not bind to the body’s other hormone receptors. Corcept is studying relacorilant in a variety of serious disorders, including ovarian, adrenal and prostate cancer and Cushing’s syndrome. Relacorilant is proprietary to Corcept and is protected by composition of matter, method of use and other patents. Relacorilant has orphan drug designation in the United States and the European Union for the treatment of Cushing’s syndrome.

About Corcept Therapeutics
For over 25 years, Corcept’s focus on cortisol modulation and its potential to treat patients across a wide variety of serious disorders has led to the discovery of more than 1,000 proprietary selective cortisol modulators. Corcept’s advanced clinical trials are being conducted in patients with hypercortisolism, solid tumors, amyotrophic lateral sclerosis (ALS) and liver disease (NASH). In February 2012, the company introduced Korlym, the first medication approved by the U.S. Food and Drug Administration for the treatment of patients with Cushing’s syndrome. Corcept is headquartered in Menlo Park, California. For more information, visit Corcept.com.

Forward-Looking Statements
Statements in this press release, other than statements of historical fact, are forward-looking statements based on our current plans and expectations that are subject to risks and uncertainties that might cause our actual results to differ materially from those such statements express or imply. These risks and uncertainties include, but are not limited to, our ability to operate our business; risks related to the study and development of Korlym as well as relacorilant, miricorilant, dazucorilant and our other product candidates, including their clinical attributes, regulatory approvals, mandates, oversight and other requirements; and the scope and protective power of our intellectual property. These and other risks are set forth in our SEC filings, which are available at our website and the SEC’s website.

In this press release, forward-looking statements include those concerning the development of relacorilant as a treatment for Cushing’s syndrome, and design, timing and expectations regarding our GRADIENT trial. We disclaim any intention or duty to update forward-looking statements made in this press release.

From https://finance.yahoo.com/news/corcept-completes-enrollment-phase-3-120000179.html

Filed under: adrenal, adrenal crisis, Cushing's, Treatments | Tagged: , , , | Leave a comment »

Delayed Diagnosis of Ectopic Cushing Syndrome

Posted on April 3, 2024 by MaryO

Abstract

Here, we present the case of a 40-year-old man in whom the diagnosis of ectopic adrenocorticotropin (ACTH) syndrome went unrecognized despite evaluation by multiple providers until it was ultimately suspected by a nephrologist evaluating the patient for edema and weight gain. On urgent referral to endocrinology, screening for hypercortisolism was positive by both low-dose overnight dexamethasone suppression testing and 24-hour urinary free cortisol measurement. Plasma ACTH values confirmed ACTH-dependent Cushing syndrome. High-dose dexamethasone suppression testing was suggestive of ectopic ACTH syndrome. Inferior petrosal sinus sampling demonstrated no central-to-peripheral gradient, and 68Ga-DOTATATE scanning revealed an avid 1.2-cm left lung lesion. The suspected source of ectopic ACTH was resected and confirmed by histopathology, resulting in surgical cure. While many patients with Cushing syndrome have a delayed diagnosis, this case highlights the critical need to increase awareness of the signs and symptoms of hypercortisolism and to improve the understanding of appropriate screening tests among nonendocrine providers.

Introduction

Even in the face of overt clinical signs and symptoms of hypercortisolism, diagnosing Cushing syndrome requires a high index of suspicion, and people with hypercortisolism experience a long road to diagnosis. In a recent meta-analysis including more than 5000 patients with Cushing syndrome, the mean time to diagnosis in all Cushing syndrome, including Cushing disease and ectopic adrenocorticotropin (ACTH) syndrome, was 34 months (1). Reasons for delayed diagnosis are multifactorial, including the nonspecific nature of subjective symptoms and objective clinical signs, as well as notorious challenges in the interpretation of diagnostic testing. Furthermore, the health care system’s increasingly organ-specific referral patterns obfuscate multisystem disorders. Improving the recognition of and decreasing time to diagnosis in Cushing syndrome are critical factors in reducing morbidity and mortality.

Here, we present the case of a patient who, despite classic signs of Cushing syndrome as well as progressive physical and mental decline, remained undiagnosed for more than 3 years while undergoing repeated evaluation by primary care and subspecialty providers. The case (1) highlights the lack of awareness of Cushing syndrome as a potential unifying diagnosis for multiorgan system problems; (2) underscores the necessity of continued education on the signs and symptoms of hypercortisolism, appropriate screening for hypercortisolism, and early referral to endocrinology; and (3) provides an opportunity for systemic change in clinical laboratory practice that could help improve recognition of pathologic hypercortisolism.

Case Presentation

In August 2018, a previously healthy 40-year-old man with ongoing tobacco use established care with a primary care provider complaining that he had been ill since the birth of his son 13 months prior. He described insomnia, headaches, submandibular swelling, soreness in his axillary and inguinal regions, and right-sided chest discomfort (Fig. 1). Previously, he had been diagnosed with sinusitis, tonsillitis, and allergies, which had been treated with a combination of antibiotics, antihistamines, and intranasal glucocorticoids. He was referred to otolaryngology where, in the absence of cervical lymphadenopathy, he was diagnosed with sternocleidomastoid pain with recommendations to manage conservatively with stretching and massage. A chest x-ray demonstrated a left apical lung nodule. Symptoms continued unabated throughout 2019, now with a cough. Repeat chest x-ray demonstrated opacities lateral to the left hilum that were attributed to vascular structures.

 

Figure 1.

Timeline of development of subjective symptoms and objective clinical findings preceding diagnosis and surgical cure of ectopic Cushing syndrome.

In May 2020, increasingly frustrated with escalating symptoms, the patient transitioned care to a second primary care provider and was diagnosed with hypertension. He complained of chronic daily headaches that prompted brain imaging with magnetic resonance imaging (MRI), which noted findings consistent with left maxillary silent sinus syndrome. He was sent back to otolaryngology, which elected to proceed with sinus surgery. During this time, he suffered a fibular fracture for which he was evaluated by orthopedic surgery. In the second half of 2020, he was seen by neurology to evaluate his chronic headaches and paresthesias with electromyography demonstrating a left ulnar mononeuropathy consistent with cubital tunnel syndrome. His primary care provider diagnosed him with fibromyalgia for which he started physical therapy, and he was referred to a pain clinic for cognitive behavioral therapy. Unfortunately his wife, dealing with her husband’s increasing cognitive and personality changes including irritability and aggression, filed for divorce.

At the end of 2020, the patient developed bilateral lower extremity edema and was prescribed hydrochlorothiazide, subsequently developing hypokalemia attributed to diuretic use. With worsening bilateral lower extremity edema and new dyspnea on exertion, he was evaluated for heart failure with an echocardiogram, which was unremarkable. Over the next several months, he gained approximately 35 pounds (∼16 kg). It was in the setting of weight gain that he was first evaluated for hypercortisolism with random serum cortisol of 22.8 mcg/dL (629 nmol/L) and 45.6 mcg/dL (1258 nmol/L) in the late morning and mid-day, respectively. No reference range was provided for the times of day at which these laboratory values were drawn. Although these serum cortisol values were above provided reference ranges for other times of day, they were not flagged as abnormal by in-house laboratory convention, and they were overlooked. The search for other etiologies of his symptoms continued.

In early 2021, diuretic therapy and potassium supplementation were escalated for anasarca. He developed lower extremity cellulitis and received multiple courses of antibiotics. Skin biopsy performed by dermatology demonstrated disseminated Mycobacterium and later Serratia (2), prompting referral to infectious disease for management. Additional subspecialty referrals included rheumatology (polyarthralgia) and gastroenterology (mildly elevated alanine transaminase with planned liver biopsy). In July 2021, he was evaluated for edema by nephrology, where the constellation of subjective symptoms and objective data including hypertension, central weight gain, abdominal striae, fracture, edema, easy bruising, medication-induced hypokalemia, atypical infections, and high afternoon serum cortisol were noted, and the diagnosis of Cushing syndrome was strongly suspected. Emergent referral to endocrinology was placed.

Diagnostic Assessment

At his first clinic visit with endocrinology in June 2021, the patient’s blood pressure was well-controlled on benazepril. Following weight gain of 61 pounds (∼28 kg) in the preceding 2 years, body mass index was 33. Physical examination demonstrated an ill-appearing gentleman with dramatic changes when compared to prior pictures (Fig. 2), including moon facies, dorsocervical fat pad, violaceous abdominal striae, weeping lower extremity skin infections, an inability to stand without assistance from upper extremities, and depressed mood with tangential thought processes.

 

Figure 2.

Photographic representation of physical changes during the years leading up to diagnosis of ectopic Cushing syndrome in June 2021 and after surgical resection of culprit lesion.

Diagnostic workup for hypercortisolism included a morning cortisol of 33.4 mcg/dL (922 nmol/L) (normal reference range, 4.5-22.7 mcg/dL) and ACTH of 156 pg/mL (34 pmol/L) (normal reference range, 7.2-63 pg/mL) following bedtime administration of 1-mg dexamethasone, and 24-hour urine free cortisol of 267 mcg/24 hours (737 nmol/24 hours) (normal reference range, 3.5-45 mcg/24 hours). Morning serum cortisol and plasma ACTH following bedtime administration of 8-mg dexamethasone were 27.9 mcg/dL (770 nmol/L) and 98 pg/mL (22 pmol/L), respectively. Given concern for potential decompensation, he was hospitalized for expedited work-up. Brain MRI did not demonstrate a pituitary lesion (Fig. 3), and inferior petrosal sinus sampling under desmopressin stimulation showed no central-to-peripheral gradient (Table 1). He underwent a positron emission tomography–computed tomography 68Ga-DOTATATE scan that demonstrated a 1.2-cm left pulmonary nodule with radiotracer uptake (Fig. 4).

 

Figure 3.

A, Precontrast and B, postcontrast T1-weighted sagittal magnetic resonance imaging of the sella. Images were affected by significant motion degradation, precluding clear visualization of the pituitary gland on coronal imaging.

 

Figure 4.

68Ga-DOTATATE imaging. A, Coronal and B, axial views of the chest after administration of radiopharmaceutical. Arrow in both panels indicates DOTATATE-avid 1.2-cm left lung lesion.

 
Table 1.

Bilateral petrosal sinus and peripheral adrenocorticotropin levels preintravenous and postintravenous injection of desmopressin acetate 10 mcg

Time post DDAVP, min Left petrosal ACTH Left petrosal:peripheral ACTH Right petrosal ACTH Right petrosal:peripheral ACTH Peripheral ACTH Left:right petrosal ACTH
0 172 pg/mL
(37.9 pmol/L)		 1.1 173 pg/mL
(38.1 pmol/L)		 1.2 150 pg/mL
(33.0 pmol/L)		 1.0
3 288 pg/mL
(63.4 pmol/L)		 1.8 292 pg/mL
(64.3 pmol/L)		 1.8 162 pg/mL
(35.7 pmol/L)		 1.0
5 348 pg/mL
(76.6 pmol/L)		 1.8 341 pg/mL
(75.1 pmol/L)		 1.8 191 pg/mL
(42.1 pmol/L)		 1.0
10 367 pg/mL
(80.8 pmol/L)		 1.3 375 pg/mL
(82.6 pmol/L)		 1.3 278 pg/mL
(61.2 pmol/L)		 1.0

Abbreviations: ACTH, adrenocorticotropin; DDAVP, desmopressin acetate.

Treatment

The patient was started on ketoconazole 200 mg daily for medical management of ectopic ACTH-induced hypercortisolism while awaiting definitive surgical treatment. Within a month of initial endocrinology evaluation, he underwent thoracoscopic left upper lobe wedge resection with intraoperative frozen histopathology section consistent with a well-differentiated neuroendocrine tumor and final pathology consistent with a well-differentiated neuroendocrine tumor. Staining for ACTH was positive (Fig. 5). Postoperative day 1 morning cortisol was 1.4 mcg/dL (39 nmol/L) (normal reference range, 4.5-22.7 mcg/dL). He was started on glucocorticoid replacement with hydrocortisone and was discharged from his surgical admission on hydrocortisone 40 mg in the morning and 20 mg in the afternoon.

 

Figure 5.

Lung tumor histopathology. A, The tumor was epicentered around a large airway (asterisk) and showed usual architecture for carcinoid tumor. B, The tumor cells had monomorphic nuclei with a neuroendocrine chromatin pattern, variably granulated cytoplasm, and a delicate background vascular network. By immunohistochemistry, the tumor cells were strongly positive for C, synaptophysin; D, CAM5.2; and E, adrenocorticotropin. F, Ki-67 proliferative index was extremely low (<1%).

Outcome and Follow-up

Approximately 12 days after discharge, the patient was briefly readmitted from the skilled nursing facility where he was receiving rehabilitation due to a syncopal event attributed to hypovolemia. This was felt to be secondary to poor oral intake in the setting of both antihypertensive and diuretic medications as well as an episode of emesis earlier in the morning precluding absorption of his morning hydrocortisone dose. Shortly after this overnight admission, he was discharged from his skilled nursing facility to home. In the first month after surgery, he lost approximately 30 pounds (∼14 kg) and had improvements in sleep and mood.

Eight months after surgery, hydrocortisone was weaned to 10 mg daily. Cosyntropin stimulation testing holding the morning dose showed 1 hour cortisol 21.5 mcg/dL (593 nmol/L). Hydrocortisone was subsequently discontinued. In June 2022, 1 year following surgery, 3 sequential midnight salivary cortisol tests were undetectable. At his last visit with endocrinology in June 2023, he felt well apart from ongoing neuropathic pain in his feet and continued but improved mood disturbance. Though his health has improved dramatically, he continues to attribute his divorce and substantial life disruption to his undiagnosed hypercortisolism.

Discussion

Endogenous neoplastic hypercortisolism encompasses a clinical spectrum from subclinical disease, as is common in benign adrenal cortical adenomas, to overt Cushing syndrome of adrenal, pituitary, and ectopic origin presenting with dramatic clinical manifestations (3) and long-term implications for morbidity and mortality (4). Even in severe cases, a substantial delay in diagnosis is common. In this case, despite marked hypercortisolism secondary to ectopic ACTH syndrome, the patient’s time from first symptoms to diagnosis was more than 3 years, far in excess of the typical time to diagnosis in this subtype, noted to be 14 months in 1 study (1).

He initially described a constellation of somatic symptoms including subjective neck swelling, axillary and inguinal soreness, chest discomfort, and paresthesias, and during the year preceding diagnosis, he developed hypertension, fibular fracture, mood changes, weight gain, peripheral edema, hypokalemia, unusual infections, and abdominal striae. Each of these symptoms in isolation is a common presentation in the primary care setting, therefore the challenge arises in distinguishing common, singular causes from rare, unifying etiologies, especially given the present epidemics of diabetes, obesity, and associated cardiometabolic abnormalities. By Endocrine Society guidelines, the best discriminatory features of Cushing syndrome in the adult population are facial plethora, proximal muscle weakness, abdominal striae, and easy bruising (5). Furthermore, Endocrine Society guidelines suggest evaluating for Cushing disease when consistent clinical features are present at a younger-than-expected age or when these features accumulate and progress, as was the case with our patient (5).

However, even when the diagnosis is considered, the complexities of the hypothalamic-pituitary-adrenal axis make selection and interpretation of screening tests challenging outside the endocrinology clinic. We suspect that in most such situations, a random serum cortisol measurement is far more likely to be ordered than a validated screening test, such as dexamethasone suppression testing, urine free cortisol, and late-night salivary cortisol per Endocrine Society guidelines (5). Although random serum cortisol values are not considered a screening test for Cushing syndrome, elevated values can provide a clue to the diagnosis in the right clinical setting. In this case, 2 mid-day serum cortisols were, by in-house laboratory convention, not flagged as abnormal despite the fact that they were above the upper limit of provided reference ranges. We suspect that the lack of electronic medical record flagging of serum cortisol values contributed to these values being incorrectly interpreted as ruling out the diagnosis.

Cushing syndrome remains among the most evasive and difficult diagnoses in medicine due to the doubly difficult task of considering the disorder in the face of often protean signs and symptoms and subsequently conducting and interpreting screening tests. The challenges this presents for the nonendocrinologist have recently been recognized by a group in the United Kingdom after a similarly overlooked case (6). We believe that our case serves as a vivid illustration of the diagnostic hurdles the clinician faces and as a cautionary tale with regard to the potential downstream effects of a delay in diagnosis. Standardization of clinical laboratory practices in flagging abnormal cortisol values is one such intervention that may aid the busy clinician in more efficiently recognizing laboratory results suggestive of this diagnosis. While false-positive case detection is a significant downside to this approach, given the potential harm in delayed or missed diagnosis, the potential benefits may outweigh the risks.

Learning Points

  • People with Cushing syndrome frequently experience a prolonged time to diagnosis, in part due to lack of recognition in the primary care and nonendocrine subspecialty settings of the constellation of clinical findings consistent with hypercortisolism.
  • Endocrine Society guidelines recommend against random serum cortisol as initial testing for Cushing syndrome in favor of dexamethasone suppression testing, urine free cortisol, and late-night salivary cortisol.
  • Increased awareness of Cushing syndrome by primary care providers and specialists in other fields could be an important and impactful mechanism to shorten the duration of symptom duration in the absence of diagnosis and hasten cure where cure is achievable.
  • We suggest clinical laboratories consider standardizing flagging abnormal cortisol values to draw attention to ordering providers and perhaps lower the threshold for endocrinology referral if there is any uncertainty in interpretation, especially in the context of patients with persistent symptoms and elusive diagnoses.

Acknowledgments

We are grateful to the patient for allowing us to present his difficult case to the community with the hopes of improving time to diagnosis for patients with hypercortisolism.

Contributors

All authors made individual contributions to authorship. J.M.E., E.M.Z., and K.R.K. were involved in the diagnosis and management of this patient. B.C.M., J.M.E., E.M.Z., and K.R.K. were involved in manuscript submission. S.M.J. performed and analyzed histopathology and prepared the figure for submission. All authors reviewed and approved the final draft.

Funding

No public or commercial funding.

Disclosures

J.M.E. was on the editorial board of JCEM Case Reports at the time of initial submission.

Informed Patient Consent for Publication

Signed informed consent obtained directly from the patient.

Data Availability Statement

Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.

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Abbreviations

 

  • ACTH

    adrenocorticotropin

  • MRI

    magnetic resonance imaging

© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Filed under: Cushing's, Diagnostic Testing, Rare Diseases | Tagged: , , , , | Leave a comment »

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