Fluconazole Found to Be Safe Alternative for Patient with Recurrent Cushing’s

Treatment with fluconazole after cabergoline eased symptoms and normalized cortisol levels in a patient with recurrent Cushing’s disease who failed to respond to ketoconazole, a case study reports.

The case report, “Fluconazole as a Safe and Effective Alternative to Ketoconazole in Controlling Hypercortisolism of Recurrent Cushing’s Disease: A Case Report,” was published in the International Journal of Endocrinology Metabolism.

Ketoconazole, (brand name Nizoral, among others) is an anti-fungal treatment used off-label for Cushing’s disease to prevent excess cortisol production, a distinct symptom of the disease. However, severe side effects associated with its use often result in treatment discontinuation and have led to its unavailability or restriction in many countries.

Consequently, there is a need for alternative medications that help manage disease activity and clinical symptoms without causing adverse reactions, and that could be given to patients who do not respond to ketoconazole treatment.

In this case report, researchers in Malaysia reported on a 50-year-old woman who fared well with fluconazole treatment after experiencing severe side effects with ketoconazole.

The woman had been in remission for 16 years after a transsphenoidal surgery — a minimally invasive brain surgery to remove a pituitary tumor — but went to the clinic with a three-year history of high blood pressure and gradual weight gain.

She also showed classic symptoms of Cushing’s disease: moon face, fragile skin that bruised easily, and purple stretch marks on her thighs.

Blood and urine analysis confirmed high cortisol levels, consistent with a relapse of the pituitary tumor. Accordingly, magnetic resonance imaging (MRI) of her brain showed the presence of a small tumor on the right side of the pituitary gland, confirming the diagnosis of recurrent Cushing’s disease.

Doctors performed another transsphenoidal surgery to remove the tumor, and a brain MRI then confirmed the success of the surgery. However, her blood and urine cortisol levels remained markedly high, indicating persistent disease activity.

The patient refused radiation therapy or adrenal gland removal surgery, and was thus prescribed ketoconazole twice daily for managing the disease. But after one month on ketoconazole, she experienced low cortisol levels.

Hydrocortisone — a synthetic cortisol hormone — was administered to maintain steady cortisol levels. However, she developed severe skin itching and peeling, which are known side effects of ketoconazole. She also suffered a brain bleeding episode, for which she had to have a craniotomy to remove the blood clot.

Since she experienced adverse effects on ketoconazole, which also hadn’t decreased her disease activity, the doctors switched her to cabergoline. Cabergoline (marketed as Dostinex, among others) is a dopamine receptor agonist that has been shown to be effective in managing Cushing’s disease.

But cabergoline treatment also did not lower the disease activity, and her symptoms persisted.

The doctors then added fluconazole (marketed as Diflucan, among others), an anti-fungal medication, based on studies that showed promising results in managing Cushing’s syndrome. Three months after the addition of fluconazole to her treatment plan, the patient’s clinical symptoms and cortisol levels had responded favorably.

At her next clinical visit 15 months later, her condition remained stable with no adverse events.

“This case demonstrates the long-term efficacy of fluconazole in tandem with cabergoline for the control of recurrent Cushing’s disease,” the researchers wrote.

The favorable outcome in this case also “supports the notion that fluconazole is a viable substitute for ketoconazole in the medical management of this rare but serious condition,” they concluded.

From https://cushingsdiseasenews.com/2018/09/27/fluconazole-safe-effective-alternative-recurrent-cushings-patient-case-report/

Minimally Invasive Approaches Lead to High Remission Rates in Children

Minimally invasive diagnostic methods and transnasal surgery may lead to remission in nearly all children with Cushing’s disease, while avoiding more aggressive approaches such as radiation or removal of the adrenal glands, a study shows.

The study, “A personal series of 100 children operated for Cushing’s disease (CD): optimizing minimally invasive diagnosis and transnasal surgery to achieve nearly 100% remission including reoperations,” was published in the Journal of Pediatric Endocrinology and Metabolism.

Normally, the pituitary produces adrenocorticotropic hormone (ACTH), which stimulates the adrenal glands to produce cortisol. When a patient has a pituitary tumor, that indirectly leads to high levels of cortisol, leading to development of Cushing’s disease (CD).

In transnasal surgery (TNS), a surgeon goes through the nose using an endoscope to remove a pituitary tumor. The approach is the first-choice treatment for children with Cushing’s disease due to ACTH-secreting adenomas — or tumors — in the pituitary gland.

Micro-adenomas, defined as less than 4 mm, are more common in children and need surgical expertise for removal. It is necessary to determine the exact location of the tumor before conducting the surgery.

Additionally, many surgeons perform radiotherapy or bilateral adrenalectomy (removal of both adrenal glands) after the surgery. However, these options are not ideal as they can be detrimental to children who need to re-establish normal growth and development patterns.

Dieter K. Lüdecke, a surgeon from Germany’s University of Hamburg, has been able to achieve nearly 100% remission while minimizing the need for pituitary radiation or bilateral adrenalectomy. In this study, researchers looked at how these high remission rates can be achieved while minimizing radiotherapy or bilateral adrenalectomy.

Researchers analyzed 100 patients with pediatric CD who had been referred to Lüdecke for surgery from 1980-2009. Data was published in two separate series — series 1, which covers patients from 1980-1995, and series 2, which covers 1996-2009. All the surgeries employed direct TNS.

Diagnostic methods for CD have improved significantly over the past 30 years. Advanced endocrine diagnostic investigations, such as testing for levels of salivary cortisol in the late evening and cortisol-releasing hormone tests, have made a diagnosis of CD less invasive. This is particularly important for excluding children with obesity alone from children with obesity and CD. Methods to determine the precise location of micro-adenomas have also improved.

The initial methodology to localize tumors was known as inferior petrosal sinus sampling (IPSS), an invasive procedure in which ACTH levels are sampled from the veins that drain the pituitary gland.

In series 1, IPSS was performed in 24% of patients, among which 46% were found to have the wrong tumor location. Therefore, IPSS was deemed invasive, risky, and unreliable for this purpose.

All adenomas were removed with extensive pituitary exploration. Two patients in series 1 underwent early repeat surgery; all were successful.

Lüdecke introduced intraoperative cavernous sinus sampling (CSS), an improved way to predict location of adenomas. This was found to be very helpful in highly select cases and could also be done preoperatively for very small adenomas.

In series 2, CSS was used in only 15% of patients thanks to improved MRI and endocrinology tests. All patients who underwent CSS had correct localization of their tumors, indicating its superiority over IPSS.

In series 2, three patients underwent repeat TNS, which was successful. In these recurrences, TNS minimized the need for irradiation. The side effects of TNS were minimal. Recurrence rate in series 1 was 16% and 11% in series 2.

While Lüdecke’s patients achieved a remission rate of 98%, other studies show cure rates of 45-69%. Only 4% of patients in these two series received radiation therapy.

“Minimally invasive unilateral, microsurgical TNS is important functionally for both the nose and pituitary,” the researchers concluded. “Including early re-operations, a 98% remission rate could be achieved and the high risk of pituitary function loss with radiotherapy could be avoided.”

From https://cushingsdiseasenews.com/2018/09/04/minimally-invasive-methods-yield-high-remission-in-cushings-disease-children/

ACTH test after adenomectomy may accurately predict Cushing’s disease remission

A plasma adrenocorticotropic hormone suppression test performed shortly after surgical adenomectomy may accurately predict both short- and long-term remission of Cushing’s disease, according to research published in Pituitary.

“Cushing’s disease is caused by hypersecretion of adrenocorticotropic hormone (ACTH) by a pituitary adenoma, resulting in hypercortisolism,” Erik Uvelius, MD, of the department of clinical sciences, Skåne University Hospital, Lund University, Sweden, and colleagues wrote in the study background. “Surgical adenomectomy is the first line of treatment. Postoperative remission is reported in 43% to 95% of cases depending on factors such as adenoma size, finding of pituitary adenoma on preoperative MRI and surgeons’ experience. However, there is no consensus on what laboratory assays and biochemical thresholds should be used in determining or predicting remission over time.”

In the study, the researchers retrospectively gathered data from medical records of 28 patients who presented with Cushing’s disease to Skåne University Hospital between November 1998 and December 2011, undergoing 45 transsphenoidal adenomectomies.

On postoperative days 2 and 3, oral betamethasone was administered (1 mg at 8 a.m., 0.5 mg at 2 p.m., and 0.5 mg at 8 p.m.). Researchers assessed plasma cortisol and plasma ACTH before betamethasone administration and again at 24 and 48 hours, and measured 24-urinary free cortisol on postoperative day 3.

At 3 months postoperatively and then annually, plasma concentrations of morning cortisol and ACTH along with urinary-free cortisol and/or a low-dose dexamethasone suppression test were evaluated at the endocrinologists’ discretion. The researchers defined remission as lessening of clinical signs and symptoms of hypercortisolism, as well as laboratory confirmation through the various tests.

The researchers used Youden’s index to establish the cutoff with the highest sensitivity and specificity in predicting remission over the short term (3 months) and long term (5 years or more). Clinical accuracy of the different tests was illustrated through the area under curve.

The study population consisted of mainly women (71%), with a median age of 49.5 years. No significant disparities were seen in age, sex or surgical technique between patients who underwent a primary procedure and those who underwent reoperation. Two of the patients were diagnosed with pituitary carcinoma and 11 had a macroadenoma. ACTH positivity was identified in all adenomas and pathologists confirmed two cases of ACTH-producing carcinomas.

Of the 28 patients, 12 (43%) demonstrated long-term remission at last follow-up. Three patients were not deemed in remission after primary surgery but were not considered eligible for additional surgical intervention, whereas 13 patients underwent 17 reoperations to address remaining disease or recurrence. Four patients demonstrated long-term remission after a second or third procedure, equaling 16 patients (57%) achieving long-term remission, according to the researchers.

The researchers found that both short- and long-term remission were most effectively predicted through plasma cortisol after 24 and 48 hours with betamethasone. A short-term remission cutoff of 107 nmol/L was predicted with a sensitivity of 0.85, specificity of 0.94 and a positive predictive value of 0.96 and AUC of 0.92 (95% CI, 0.85-1). A long-term remission cutoff of 49 nmol/L was predicted with a sensitivity of 0.94, specificity of 0.93, positive predictive value of 0.88 and AUC of 0.98 (95% CI, 0.95-1). This cutoff was close to the suppression cutoff for the diagnosis of Cushing’s disease, 50 nmol/L. The cutoff of 25 nmol/L showed that the use of such a strict suppression cutoff would cause a low level of true positives and a higher occurrence of false negatives, according to the researchers.

“A 48 h 2 mg/day betamethasone suppression test day 2 and 3 after transsphenoidal surgery of Cushing’s disease could safely predict short- and long-term remission with high accuracy,” the researchers wrote. “Plasma cortisol after 24 hours of suppression showed the best accuracy in predicting 5 years’ remission. Until consensus on remission criteria, it is still the endocrinologists’ combined assessment that defines remission.” – by Jennifer Byrne

DisclosuresThe authors report no relevant financial disclosures.

From https://www.healio.com/endocrinology/neuroendocrinology/news/in-the-journals/%7B0fdfb7b0-e418-4b53-b59d-1ffa3f7b8cd3%7D/acth-test-after-adenomectomy-may-accurately-predict-cushings-disease-remission

Cushing Syndrome Results in Poor Quality of Life Even After Remission

Functional remission did not occur in most patients with Cushing syndrome who were considered to be in biochemical and clinical remission, according to a study published in Endocrine. This was evidenced by their quality of life, which remained impaired in all domains.

The term “functional remission” is a psychiatric concept that is defined as an “association of clinical remission and a recovery of social, professional, and personal levels of functioning.” In this observational study, investigators sought to determine the specific weight of psychological (anxiety and mood, coping, self-esteem) determinants of quality of life in patients with Cushing syndrome who were considered to be in clinical remission.

The cohort included 63 patients with hypercortisolism currently in remission who completed self-administered questionnaires that included quality of life (WHOQoL-BREF and Cushing QoL), depression, anxiety, self-esteem, body image, and coping scales. At a median of 3 years since remission, participants had a significantly lower quality of life and body satisfaction score compared with the general population and patients with chronic diseases. Of the cohort, 39 patients (61.9%) reported having low or very low self-esteem, while 16 (25.4%) had high or very high self-esteem. Depression and anxiety were seen in nearly half of the patients and they were more depressed than the general population. In addition, 42.9% of patients still needed working arrangements, while 19% had a disability or cessation of work.

Investigators wrote, “This impaired quality of life is strongly correlated to neurocognitive damage, and especially depression, a condition that is frequently confounded with the poor general condition owing to the decreased levels of cortisol. A psychiatric consultation should thus be systematically advised, and [selective serotonin reuptake inhibitor] therapy should be discussed.”

Reference

Vermalle M, Alessandrini M, Graillon T, et al.  Lack of functional remission in Cushing’s Syndrome [published online July 17, 2018]. Endocrine. doi:10.1007/s12020-018-1664-7

From https://www.endocrinologyadvisor.com/general-endocrinology/functional-remission-quality-of-life-cushings-syndrome/article/788501/

Transsphenoidal Surgery Is Safe and Effective Treatment for Cushing’s Disease

Transsphenoidal surgery, a minimally invasive surgery to remove tumors in the pituitary gland, is safe and effective to treat Cushing’s disease, a 20-year history of cases in a Belgian hospital shows.

The surgery resulted in high remission rates (83%) in patients. It was also found to be safe, rarely leading to insufficient functioning of the pituitary gland.

The study, “Outcome of transsphenoidal surgery for Cushing’s Disease: a single-center experience over 20 years,” was published in the journal World Neurosurgery.

Surgical removal of tumors in the pituitary gland of the brain remains the gold standard for Cushing’s disease treatment.

Transsphenoidal surgery (TSS) usually leads to good remission rates ranging from 68-95%, depending on the location and type of tumor, the neurosurgeon’s expertise, follow-up period, and the definition of remission.

Today, TSS consists of surgery directed through the nose to get to the bottom of the skull, where the pituitary gland is located. The tumor is reached via the nasal cavity with no need for incisions on the face.

To address the safety and effectiveness of this type of surgery for treating Cushing’s, researchers retrospectively reviewed the outcome of 71 patients who received their first TSS at Saint-Luc Hospital, Belgium, between 1996 and 2017. Patients were followed for an average of 6.8 years (82 months).

Surgeons used a type of TSS that is image-guided with the help of a microscope which magnifies the surgeon’s vision.

Remission was defined as normal fasting cortisol level, normal 24-hour urinary-free cortisol, or prolonged need for hydrocortisone replacement for one year after surgery.

Replacement therapies are sometimes needed when the pituitary is not producing enough cortisol after surgery.

Patients were mostly women, ages 15 to 84. Some of them, 32%, required multiple surgeries.

In total, 46 patients out of 71 were in remission after the first surgery, 11 after the second surgery, one after the third, and one after the fourth intervention.

A successful first surgery, resulting in a one-year remission, was a positive indicator for patients, as it was associated with high final remission rates (95%).

However, if the first surgery failed, only 36% of patients achieved a final remission.

“Obtaining a lasting remission after a first TSS could be an interesting parameter to influence future therapeutic decisions [like] performing repeated surgery rather than choosing second-line therapies,” researchers wrote.

Overall, remission was achieved in 83% of patients who underwent a single or multiple TSS intervention, a recurrence rate comparable to previous reports.

Surgery was particularly successful for curing patients with macroadenomas — tumors larger than 10 mm — leading to a 92% remission rate.

Small tumors that were not visible on magnetic resonance imaging (MRI) scans were more difficult to treat, with only 71% of patients being cured. Still, such a remission rate was better than what is commonly reported for MRI-negative tumors. This is likely explained by a higher level of expertise by the surgeon.

Levels of cortisol one day after TSS were significantly lower in patients with long-term remission. However, high levels were still observed in a few patients, especially those who had Cushing’s disease for many years.

“Therefore, high cortisol levels in the postoperative early days do not always indicate persistent disease and later [cortisol] evaluation is warranted,” the researchers wrote.

Most complications from surgery were minor and transient, except for seven patients who developed diabetes. Only 8.8% of patients developed long-term failure of the pituitary gland, likely because physicians favored a less aggressive intervention plan to leave the pituitary gland as intact as possible.

However, such an approach may also explain why some patients had to undergo multiple surgeries to completely remove the tumor.

In addition, a longer duration of Cushing’s disease symptoms and higher cortisol levels before surgery could significantly predict a poorer likelihood of being cured by TSS.

“Neuronavigation-guided microscopic TSS is a safe and effective primary treatment for [Cushing’s disease], allowing high remission rates,” the researchers wrote.

From https://cushingsdiseasenews.com/2018/07/26/transsphenoidal-surgery-safe-effective-treatment-cushings-disease/

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