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

Posted on July 2, 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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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.

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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

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  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
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  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
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  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.
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  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
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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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Intensity-Modulated Radiotherapy for Cushing’s Disease: Single-Center Experience in 70 Patients

Posted on October 16, 2023 by MaryO

Context: Intensity-modulated radiotherapy (IMRT) is a modern precision radiotherapy technique for the treatment of the pituitary adenoma.

Objective: Aim to investigate the efficacy and toxicity of IMRT in treating Cushing’s Disease (CD).

Methods: 70 of 115 patients with CD treated with IMRT at our institute from April 2012 to August 2021 were included in the study. The radiation doses were usually 45-50 Gy in 25 fractions. After IMRT, endocrine evaluations were performed every 6 months and magnetic resonance imaging (MRI) annually. Endocrine remission was defined as suppression of 1 mg dexamethasone test (DST) or normal 24-hour urinary free cortisol level (24hUFC). The outcome of endocrine remission, endocrine recurrence, tumor control and complications were retrieved from medical record.

Results: At a median follow-up time of 36.8 months, the endocrine remission rate at 1, 2, 3 and 5 years were 28.5%, 50.2%, 62.5% and 74.0%, respectively. The median time to remission was 24 months (95%CI: 14.0-34.0). Endocrine recurrence was found in 5 patients (13.5%) till the last follow-up. The recurrence-free rate at 1, 2, 3 and 5 years after endocrine remission was 98.2%, 93.9%, 88.7% and 88.7%, respectively. The tumor control rate was 98%. The overall incidence of new onset hypopituitarism was 22.9%, with hypothyroidism serving as the most common individual axis deficiency. Univariate analysis indicated that only higher Ki-67 index (P=0.044) was significant favorable factors for endocrine remission.

Conclusion: IMRT was a highly effective second-line therapy with low side effect profile for CD patients. Endocrine remission, tumor control and recurrence rates were comparable to previous reports on FRT and SRS.

Introduction

Cushing’s disease (CD) is characterized by hypersecretion of adrenocorticotropic hormone (ACTH) from pituitary adenoma. As the state of hypercortisolemia considerably increases morbidity and mortality, normalizing cortisol levels is regarded as the major treatment goal in patients with CD (1). Transsphenoidal selective adenomectomy (TSS) is now established as the first-line treatment of CD. Despite the satisfactory remission rate that can be achieved with TSS (ranging from 59-97%), delayed recurrences have also been reported in up to 50% of patients (2).

The Endocrine Society guidelines suggest a shared decision-making approach in patients who underwent a noncurative surgery or for whom surgery was not possible (3). Second-line therapeutic options include repeat transsphenoidal surgery, medical therapy, radiotherapy and bilateral adrenalectomy. Radiotherapy (RT) is generally used in patients who have failed TSS or have recurrent CD, as well as in progressively growing or invasive corticotroph tumors (3, 4).

Both stereotactic radiosurgery(SRS)and fractionated radiotherapy (FRT) have been used in the treatment of CD. Conventional radiotherapy as one of the technique for FRT has been used with a long experience, but its benefits were hindered by high risk of toxicity, mainly attributed to the harm to healthy surrounding structures (4). Previous studies on conventional RT in treating CD showed high efficacy (tumor control rate of 92-100% and hormonal control rate of 46-89%), but RT-induced hypopituitarism (30-58%) and recurrence (16-21%) were also commonly reported (1, 4–7). Modern precise radiotherapy, especially intensity-modulated radiotherapy (IMRT), can spare the surrounding normal structure better by a more conformal and precise dose distribution (8). However, a large cohort study on long-term efficacy and toxicity of IMRT for CD is still lacking. Therefore, in the current study, we aim to analyze the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) in treating CD. We also investigated the predictors of endocrine remission in aid of further management.

Methods

Patient

We collected 115 cases of Cushing’s disease treated at our center from April 2012 to August 2021. Patients were excluded under the following conditions: (1) follow-up time less than 3 months, (2) lacking evaluation of serum cortisol (F), adrenocorticotropic hormone (ACTH) or 24-hour urinary free cortisol (24hUFC) before or after RT, (3) underwent uni or bilateral adrenalectomy, (4) having received RT at other institutes before admitted to our center. At last, a total of 70 cases were included in this study.

Radiotherapy parameters

RT was administrated by a linear accelerator (6 MV X-ray). Intensity-modulated radiation therapy was applied for all patients. Including fix-filde IMRT (FF-IMRT), volumetric modulated arc therapy (VMAT) or Tomotherapy. We immobilized the patient with an individualized thermoplastic head mask and then conducted a computed tomography (CT) simulation scan at 2- to 3-mm intervals. The target volume and organs at risks (OARs) were delined with a contrast enhanced T1-weighted image (T1WI) magnetic resonance imaging (MRI) fusing with planning CT. The gross tumor volume (GTV) was defined with the lesion visible on MRI or CT. The clinical target volume (CTV) included microscopic disease, especially when the tumor invaded cavernous sinus and surrounding bones. The planning target volume (PTV) was defined as CTV plus a margin of 2- to 3-mm in three dimensions. The prescription dose was defined at 100% isodoseline to cover at least 95% PTV. The maximum dose was limited to less than 54 Gy for the brain stem and optic pathway structures. Radiotherapy was performed once a day and five fractions a week during five to six weeks. The total dose was 45-60 Gy, delivered in 25-30 fractions, with most patients (78.6%) receiving 45-50 Gy in 25 fractions. The fractionated dose was 1.8-2.0 Gy.

Data collection and clinical evaluation

Baseline characteristics were collected at the last outpatient visit before RT, including demographic characteristics, biochemical data, tumor characteristics and details of previous treatments. After RT, endocrine evaluations were performed every 6 months. Endocrine remission was considered when 1 mg dexamethasone suppression test (DST)<1.8 mg/dl. If 1mg DST results were lacking, then 24hUFC within the normal range was used as a remission criterion. Patients who regained elevated hormone levels after achieving remission were considered to have endocrine recurrence. For patients receiving medications that could interfere with the metabolism of cortisol, hormonal evaluation was performed at least 3 months after the cessation of the therapy.

Tumor size was measured on magnetic resonance imaging (MRI) before RT and annually after the completion of RT. Any reduction in or stabilization of tumor size was considered as tumor control. Tumor recurrence was defined as an increase of 2 millimeters in 2 dimensions comparing to MRI before RT, or from invisible tumor to a visible tumor on MRI (9).

Anterior pituitary function was assessed before RT and every 6 months during the follow-up after RT. RT-induced hypopituitarism was defined as the development of new onset hormone deficiency after RT. The diagnostic criteria for growth hormone deficiency (GHD), central hypothyroidism and hypogonadotropic hypogonadism (HH) refer to previous literature (10–12). Panhypopituitarism referred to three or more anterior pituitary hormone deficiencies (13).

Statistical analysis

Statistical analysis was performed with SPSS version 25.0. Longitudinal analysis was performed with Kaplan-Meier method. For time-dependent variable, Log rank test was used for univariate analysis and Cox regression for multivariate analysis. The cut-off of F, ACTH and 24hUFC were defined as their median value. All variants in the univariate analysis were included in the model of multivariate analysis. P value < 0.05 was considered statistically significant. Plot was created with GraphPad Prism version 9.4.

Results

Patient characteristics

Of 70 cases included in the study, the median age was 32 years (range, 11-66 years). 60 (85.7%) were female and 10 (14.3%) were male (F:M= 6:1). The median follow-up time was 36.8 months (range, 3.0-111.0 months). 68 patients received RT as a second-line treatment because of incomplete tumor resection, failure to achieve complete endocrine remission or recurrence postoperative, and 2 were treated with RT alone because of contraindication of surgery. The frequency of surgical treatment was 1 for 42 patients, 2 for 21 and more than 3 for 5. A total of 8 patients received medical treatment before RT. 5 of them used pasireotide, 2 used ketoconazole and 1 used mifepristone. The median ACTH level was 58.7 pg/ml (range 14.9-265 pg/ml), F, 26.2μg/dl (range 11.8-72.6 μg/dl) and 24hUFC, 355.7 μg/24hr (range 53.5-3065 μg/24hr) before RT. Tumor size evaluation was performed in all 70 patients before RT. Among them, 36 patients showed no visible residual tumor identified on MRI and only 5 patients showed tumor size more than 1 cm. Hypopituitarism was found in 31 patients (38.8%) before RT. HH was the most common (21 patients, 26.3%), followed by central hypothyroidism (13 patients, 16.3%) and GHD (9 patients, 11.3%). Panhypopituitarism was found in 4 patients (5.0%). (Table 1).

Table 1
www.frontiersin.orgTable 1 Patient characteristics.

Endocrine remission

Endocrine remission was achieved in 37 of 70 patients during the follow-up. Six of them were evaluated by 1mg DST. The hormonal remission rate at 1, 2, 3 and 5 years were 28.5%, 50.2%, 62.5% and 74.0%, respectively, gradually increasing with follow-up time (Figure 1). The median time to remission was 24.0 months (95%CI: 14.0-34.0 months). Univariate analysis indicated that only higher Ki-67 index (P=0.044) was significant favorable factors for endocrine remission. There was no significant correlation between remission and age, sex, tumor size, the frequency of surgery, medication prior RT. The hormone levels (F, ACTH and 24hUFC prior RT) were divided into high and low groups by the median value, and were also not found to be associated with endocrine remission (Table 2). Since only Ki-67 was significant in the univariate analysis and all other parameters were far from significant, a multivariate analysis was no longer performed.

Figure 1
www.frontiersin.orgFigure 1 Endocrine remission rate during the follow-up after RT.

Table 2
www.frontiersin.orgTable 2 Univariate predictors of endocrine remission.

Endocrine recurrence was found in 5 patients till the last follow-up, with an overall recurrence rate of 13.5% (5/37). The median time to recurrence after reaching endocrine remission was 22.5 months. The recurrence-free rate at 1, 2, 3 and 5 years after endocrine remission was 98.2%, 93.9%, 88.7% and 88.7%, respectively (Figure 2).

Figure 2
www.frontiersin.orgFigure 2 Recurrence free rate after endocrine emission.

Tumor control

A total of 51 patients had repeated MRI examinations before and after treatment. During the follow-up, 20 patients showed reduction and 30 patoents remained stable in tumor size, with a tumor control rate of 98%. Only 1 patient showed enlargement tumor 1 year after RT, with F, ACTH and 24hUFC increase continuously.

Complications

At the last follow-up, 16 patients developed new onset hypopituitarism after RT. The overall incidence of RT-induced hypopituitarism was 22.9%. Hypothyroidism was the most common of hypopituitarism (8 patients), followed by HH (7 patients), adrenal insufficiency (4 patients) and GHD (3 patients). Only 1 patient (1.3%) with systemic lupus erythematosus (SLE) comorbidity complained of progressively worsening visual impairment during the follow up. No cerebrovascular event or radiation associated intracranial malignancy was found in our cohort.

Discussion

Efficacy and radiotherapy techniques

RT has been emerged as an effective second-line treatment for CD for many years. Although conventional fractionated RT has been used for a long experience in patients with CD, study on the modern precise radiotherapy, particularly IMRT, is rare and reports limited evidence on its long-term treatment outcome. IMRT can be implemented in many different techniques, such as fixed-field intensity-modulated radiotherapy (FF-IMRT), volumetric-modulated arc therapy (VMAT) and tomotherapy. Compared with conventional RT, IMRT allows a better target volume conformity while preserves adequate coverage to the target (14, 15). Our study reported that IMRT for CD has an endocrine remission rate of 74.0% at 5 years, with a median time to remission of 24.0 months (95%CI: 14.0-34.0 months). The endocrine remission rate at 5 years was comparable to those reported in previous series of FRT, with a median time to remission within the reported range (4.5-44 months) (9, 16–18) (Table 3). Compared with SRS in treating CD, the endocrine remission rate and median time to remission were also similar. Pivonello et al (19) summarized 36 studies of SRS for CD between 1986 to 2014, the mean endocrine remission rate was 60.8% and the median time to remission was 24.5 months. Tumor control rate was 98% in our cohort, only one patient showed enlargement tumor with elevating hormones. This local control rate was also comparable to that reported in a series of pituitary adenoma treated with FRT (93-100%) and SRS(92-96%) (9, 16–18, 20, 21). Indeed, despite the lack of controlled studies about SRS and FRT in treating CD, many reviews that summarize the biochemical control and tumor contral of both are similar (2, 6, 19).

Table 3
www.frontiersin.orgTable 3 Literature review of FRT and SRS in patients with CD published in recent years.

The overall endocrine recurrence rate in our study was 13.5%, with a median time to recurrence of 22.5 months. We, for the first time, reported the actuarial recurrence free rate at 1, 2, 3 and 5 years in CD patients treated with IMRT. The recurrence free rate at 3 and 5 years was 88.7% in our study. Outcomes were comparable to those reported in patients treated with conventional RT or SRS, with a mean recurrence rate and a median recurrence time of 15.9% (range, 0-62.5%) and 28.1 months, or 12.3% (range, 0-100%) and 33.5 months, according to a review conducted by Pivonello et al (19).

At 2020, we reported the outcomes of pituitary somatotroph adenomas treated with IMRT at our institution (20). Compared with pituitary somatotroph adenomas, CD has a similar 5-year remission rate (74.0% vs 74.3%) but a shorter median time to remission (24.0m vs 36.2m) (Figure 3). The tumor contral rates were similar, at 98% and 99%, respectively. The endocrine recurrence rate was significantly different, with CD being about one-fold higher than the pituitary somatotroph adenoma (13.8% vs 6.1%). This may be due to the majority of microadenomas in CD and that of macroadenomas in pituitary somatotroph adenomas.

Figure 3
www.frontiersin.orgFigure 3 Endocrine remission rate of CD and pituitary somatotroph adenoma.

Predictors of endocrine remission

In the univariate analysis, we found that only Ki-67 index ≥ 3% was correlated with better endocrine remission (p=0.044). Cortisol levels before RT and tumor size were not predictors of endocrine remission. For surgery in treating CD, higher preoperative ACTH level was considered as unfavorable prognostic factor for endocrine remission in a few studies (22, 23). For radiotherapy, some previous studies also have reported a faster endocrine remission in patients with lower serum cortisol level. Minniti et al. reported that hormone level was normalized faster in patients with lower urinary and plasma cortisol level at the time of RT (16). Apaydin also reported that low postoperative cortisol and 1mg DST was a favorable factors for faster remission in patients treated with gamma knife surgery (GKS) and hypofractionated radiotherapy (HFRT), although no significant relationship was found between remission rate and plasma cortisol level prior RT in both studies (9, 16). Castinetti et al. found that initial 24hUFC was a predicative factor of endocrine remission in patients treated with GKS, which was not reported in our cohort treated with IMRT (24). However, the discrepancy between the results can be attributed to various factors, including selection bias of retrospective study, duration of follow-up, endocrine remission criteria and cut-off value.

Tumor size before RT was considered as a significant predictor for endocrine remission in some published series of patients treated with SRS. Jagannathan et al. reported a significant relationship between preoperative tumor volume and endocrine remission in patients with CD treated with GKS (25). However no significant correlation between tumor size and endocrine remission was found in series of patients treated with FRT (5, 9, 16, 17). But our study found no significant correlation between tumor size (visible or no-visible residual tumor on MRI) before RT and endocrine remission. The frequency of surgery before RT was also not found to be associated with endocrine remission in our study, which reached a similar conclusion with some previous studies (9, 17, 18, 26). Abu Dabrh et al. reported a higher remission rate in patients receiving TSS prior RT in their meta-analysis (5). Similar result was also reported in a review on the treatment outcome of GKS in patients with CD, that postoperative GKS was more effective than primary GK (19). However, analysis on this parameter was difficult in our cohort considering the low number of patients who received IMRT as the first-line treatment.

Reports on the effect of medical treatment on endocrine remission have been controversial. Some studies reported a negative effect of medical treatment at the time of SRS on endocrine remission in patients with CD. Castinetti et al. showed a significant higher rate of endocrine remission in patients who were not receiving ketoconazole at the time of GKS, compared to those who were (27). Sheehan et al. also found a significantly shorter time to remission in patients who discontinued ketoconazole at the time of GKS (28). However, no such correlation was found in patients treated with FRT (9, 17). Like previous studies on FRT, we also noted no significant relationship between preradiation use of medication and endocrine remission, but our statistical analysis may be hindered by the low proportion of patients undergoing medical treatment before RT. Moreover, the anticortisolic drugs used in previous studies were mainly ketoconazole or cabergoline, while most of our patient have received pasireotide, whose effect have not been well-studied yet. Further studies are necessary to understand the effect of somatostatin receptor ligands on the outcome of radiotherapy in patients with CD.

Complications

Hypopituitarism is the most common complication secondary to radiotherapy, with the rate of new-onset hypopituitarism ranging widely in previous report. Pivonello et al. reviewed series of CD patients who were treated with conventional RT with a follow-up of at least 5 years (19). The reported mean and median rates of hypopituitarism were 50% and 48.3%, respectively (range, 0-100%). As regards FRT, the overall rate of new-onset hypopituitarism was 22.2-40% at a median follow-up ranging from 29-108 months, with both incidence and severity increasing with longer follow-up (9, 16–19). The incidence of hypopituitarism in our series was 22.9%, which was within the reported range of new onset hypopituitarism after FRT. Lower rate of hypopituitarism after SRS compared to conventional RT has been recognized in previous reviews (2, 6). Our study showed that new onset hypopituitarism was less prevalent after IMRT than after conventional RT. This can be attributed to a higher precision in contouring the target volume and OARs, allowing these modern radiotherapy techniques to provide a better protection to hypothalamus-pituitary axes. In previous studies, potential risk factors for new onset hypopituitarism included suprasellar extension, higher radiation dose to the tumor margin and lower isodose line prescribed (29, 30). Sensitivity of individual hormonal axes to RT varies in different series. In our study, central hypothyroidism was the most common individual axis deficiency, followed by HH, adrenal insufficiency and GHD. This sequence was similar to that reported by Sheehan et al., whose series included 64 CD patients treated with SRS, as well as some other series (29, 31). It is noted in some studies that GHD is the most vulnerable axes (19, 32, 33). Limited number of patients undergoing stimulation test may underestimate the prevalence of GHD in our study and some previous series, and longer follow-up is needed to generate a more accurate, time-dependent rate of new onset hypopituitarism.

In our study, only one patient complained of mild visual impairment, which was comparable to the rate ranging from 0-4.5% in previous series of FRT treating pituitary adenoma (9, 16–18, 26, 32, 34, 35). This patient had concomitant SLE and the associated microangiopathy may render the optic nerve intolerant to radiotherapy. Cranial nerve damage was acknowledged as an uncommon complication, with an estimated risk of vision deterioration below 1% if single radiation dose was no more than 2.0 Gy and total dose no more than 45-50 Gy (2, 36). The actuarial rate of optic neuropathy at 10 years was 0.8% in a series containing 385 patients with pituitary adenoma (37). No patient in our cohort developed cerebrovascular accident or secondary brain tumor. This finding was consistent with the low actuarial prevalence of these complications reported in other published series of FRT. Secondary brain tumor was extremely rare after SRS, with an overall incidence of 6.80 per patients-year, or a cumulative incidence of 0.00045% over 10 years in a multicenter cohort study containing 4905 patients treated with GKS (38). Ecemis et al. reviewed cohort studies of conventional RT in treating pituitary adenoma from 1990 to 2013 and found that 1.42% of patients developed secondary brain tumor, with a latency period of 19.6 years for meningioma, 11 years for glioma and 9 years for astrocytoma (39). As for cerebrovascular accident, Minniti et al. reported two patients (in a total of 40 patients) who had stroke 6 and 8 years after FRT (16). Data was still limited for FRT. Considering the low incidence and long latency period, large, controlled cohort study with long follow-up of FRT is still needed to accurately evaluate these complications.

Limitations

Our study has several limitations. First, not all patients rigorously followed regular follow-up time points, making time-dependent statistical analysis less accurate. In addition, the excessively low number of cases with 1mg DST as the endocrine remission criterion may affect the accuracy of the remission rate.Moreover, a median follow-up time of about 3 years hampered evaluation on some late complications, including cerebrovascular events and secondary brain tumor.

In conclusion, our study revealed that IMRT was a highly effective second-line therapy with low side effect profile for CD patients, and it’s endocrine remission, tumor control and recurrence rates were comparable to previous reports on FRT and SRS.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Author contributions

1. Conceptualization: FZ and HZ 2. Data curation: XL and ZX. 3. Funding acquisition: FZ. 4. Investigation: XL and ZX 5. Methodology: WW 6. Resources: XL, SS and XH 7. Validation: LL and HZ. 8. Writing – original draft: ZX 9. Writing – review and editing: XL. All authors contributed to the article and approved the submitted version.

Funding

Supported by grants National High Level Hospital Clinical Research Funding (No.2022-PUMCH-B-052) and National Key R&D Program of China, Ministry of Science and Technology of the People’s Republic of China.(Grant No. 2022YFC2407100, 2022YFC2407101).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: cushing’s disease, intensity-modulated radiotherapy, radiotherapy, pituitary adenoma, ACTH

Citation: Lian X, Xu Z, Sun S, Wang W, Zhu H, Lu L, Hou X and Zhang F (2023) Intensity-modulated radiotherapy for cushing’s disease: single-center experience in 70 patients. Front. Endocrinol. 14:1241669. doi: 10.3389/fendo.2023.1241669

Received: 17 June 2023; Accepted: 31 August 2023;
Published: 26 September 2023.

Edited by:

Luiz Augusto Casulari, University of Brasilia, Brazil

Reviewed by:

Luiz Eduardo Armondi Wildemberg, Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Brazil
Carolina Leães Rech, Federal University of Health Sciences of Porto Alegre, Brazil

Copyright © 2023 Lian, Xu, Sun, Wang, Zhu, Lu, Hou and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Fuquan Zhang, zhangfq@pumch.cn

†These authors have contributed equally to this work

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

From https://www.frontiersin.org/articles/10.3389/fendo.2023.1241669/full

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Pituitary Surgery Outcome in Patients 75 Years and Older

Posted on October 5, 2023 by MaryO

Abstract

Background

As the population ages, the number of elderly patients with an indication for pituitary surgery is rising. Information on the outcome of patients aged over 75 is limited. This study reports a large series assessing the feasibility of surgical resection in this specific age range, focusing on surgical complications and postoperative results.

Methods

A retrospective cohort study of patients with pituitary adenomas and Rathke’s cleft cysts was conducted. All patients were aged 75 years or over and treated by a single expert neurosurgical team. A control population included 2379 younger adult patients operated by the same surgeons during the same period.

Results

Between 2008 and 2022, 155 patients underwent surgery. Indication was based on vision impairment in most patients (79%). Median follow-up was 13 months (range: 3–96). The first surgery was performed with an endoscopic transsellar approach, an extended endonasal transtuberculum approach and a microscopic transcranial approach in 96%, 3%, and 1% of patients, respectively. Single surgery was sufficient to obtain volume control in 97% of patients. From Kaplan-Meier estimates, 2-year and 5-year disease control with a single surgery were 97.3% and 86.2%, respectively. Resection higher than 80% was achieved in 77% of patients. No vision worsening occurred. In acromegaly and Cushing’s disease, endocrine remission was obtained in 90% of non-invasive adenomas. Surgical complications were noted in 5% of patients, with 30-day mortality, hematoma, cerebrospinal fluid leak, meningitis, and epistaxis occurring in 0.6%, 0.6%, 1.9%, 0.6%, and 1.3% respectively. New endocrine anterior deficits occurred in only 5%, while no persistent diabetes insipidus was noted. Compared with younger patients, the complication rate was not statistically different.

Conclusions

Surgery beyond the age of 75, mainly relying on an endoscopic endonasal transsellar approach, is effective and safe, provided that patients are managed in tertiary centers.

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Abbreviations

CSF:
Cerebrospinal fluid
ASA:
American Society of Anesthesiologists Physical Status Classification System

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Author information

Authors and Affiliations

  1. Department of Neurosurgery, La Pitié-Salpêtrière University Hospital, Assistance Publique-Hôpitaux de Paris, 47-83 Boulevard de L’Hôpital, 75013, Paris, France

    Marta Garvayo, Vincent Reina, Stephan Gaillard & Bertrand Baussart

  2. Department of Neurosurgery, University Hospital of Lausanne and University of Lausanne, Lausanne, Switzerland

    Marta Garvayo & Mahmoud Messerer

  3. Université Paris Cité, CNRS, INSERM, Institut Cochin, 75014, Paris, France

    Chiara Villa, Anne Jouinot, Jérôme Bertherat, Guillaume Assié & Bertrand Baussart

  4. Department of Neuropathology, La Pitié-Salpêtière University Hospital, AP-HP, Sorbonne University, Paris, France

    Chiara Villa

  5. Department of Endocrinology, Assistance Publique-Hôpitaux de Paris, Hôpital Ambroise Paré, Boulogne Billancourt, France

    Mirella Hage & Marie-Laure Raffin-Sanson

  6. Université de Versailles Saint-Quentin-en-Yvelines UFR Des Sciences de La Santé Simone Veil, Montigny-Le-Bretonneux, France

    Mirella Hage & Marie-Laure Raffin-Sanson

  7. Department of Endocrinology and Reproductive Medicine, Centre de Référence Des Maladies Endocriniennes Rares de La Croissance Et du Développement, CRMERC, Endo-ERN, Pitié-Salpêtrière Hospital, AP-HP, Sorbonne University, Paris, France

    Carine Courtillot & Anne Bachelot

  8. Université Paris-Saclay, Inserm, Physiologie Et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d’Endocrinologie Et Des Maladies de La Reproduction, Centre de Référence des Maladies Rares de L’Hypophyse, Le Kremlin-Bicêtre, France

    Peter Kamenicky & Philippe Chanson

  9. Sorbonne University, Endocrine Unit, Reproductive Medicine, Centre de Référence Des Maladies Endocriniennes Rares de La Croissance Et du Développement (CRMERC), Endo-ERN (Id 739527), Saint-Antoine Hospital, AP-HP, Paris, France

    Camille Vatier & Sophie Christin-Maitre

  10. Inserm UMRS938, Saint-Antoine Research Center, Sorbonne University, 75012, Paris, France

    Camille Vatier

  11. INSERM UMR-833, Trousseau Hospital, Paris, France

    Sophie Christin-Maitre

  12. Department of Endocrinology, Center of Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France

    Jérôme Bertherat & Guillaume Assié

Corresponding author

Correspondence to Bertrand Baussart.

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Conflict of interest

The authors declare no competing interests.

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From https://link.springer.com/article/10.1007/s00701-023-05809-x

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