Decreasing mortality and changes in treatment patterns in patients with acromegaly from a nationwide study.

CONTEXT: New therapeutic strategies have developed for the management of acromegaly over recent decades. Whether this has improved mortality has not been fully elucidated. OBJECTIVE: The primary aim was to investigate mortality in a nationwide unselected cohort of patients with acromegaly. Secondary analyses included time trends in mortality and treatment patterns. DESIGN: A total of 1089 patients with acromegaly were identified in Swedish National Health Registries between 1987 and 2013. To analyse time trends, the cohort was divided into three periods (1987-1995, 1996-2004 and 2005-2013) based on the year of diagnosis. MAIN OUTCOME MEASURES: Using the Swedish population as reference, standardized mortality ratios (SMRs) were calculated with 95% confidence intervals (CIs). RESULTS: Overall SMR was 2.79 (95% CI: 2.43-3.15) with 232 observed and 83 expected deaths. Mortality was mainly related to circulatory diseases (SMR: 2.95, 95% CI: 2.35-3.55), including ischemic heart disease (2.00, 1.35-2.66) and cerebrovascular disease (3.99, 2.42-5.55) and malignancy (1.76, 1.27-2.26). Mortality decreased over time, with an SMR of 3.45 (2.87-4.02) and 1.86 (1.04-2.67) during the first and last time period, respectively (P = .015). During the same time periods, the frequency of pituitary surgery increased from 58% to 72% (P < 0.001) and the prevalence of hypopituitarism decreased from 41% to 23% (P < 0.001). CONCLUSIONS: Excess mortality was found in this nationwide cohort of patients with acromegaly, mainly related to circulatory and malignant diseases. Although still high, mortality significantly declined over time. This could be explained by the more frequent use of pituitary surgery, decreased prevalence of hypopituitarism and the availability of new medical treatment options.

Hypopituitarism after gamma knife radiosurgery for pituitary adenoma.

PURPOSE: The aim of the study was to investigate the incidence of and risk factors for hypopituitarism after gamma knife radiosurgery (GKRS) for pituitary adenoma. MATERIALS AND METHODS: We conducted a retrospective analysis of the pituitary function of 90 patients who underwent GKRS for pituitary adenoma at the University Hospital Centre Zagreb between 2003 and 2014. Twenty seven of them met the inclusion criteria and the others were excluded from the study due to pituitary insufficiency which was present before GKRS. Eighteen patients had non-functioning and 9 patients had secretory adenomas. Median patients' age was 56 years (24-82). GKRS was performed using the Leksell gamma knife Model C. The median prescription radiation dose was 20 Gy (15-25) and the median tumor volume size was 3.4 cm3 (0.06-16.81). New onset hypopituitarism was defined as a new deficit of one of the three hormonal axes (corticotroph, thyreotroph, or gonadotroph) ≥3 months following GKRS. SPSS was used for statistical analysis, with the significance level at P<0.05. RESULTS: During the median follow-up period of 72 months (range 6-144), 30% of patients developed new hypopituitarism after GKRS. This corresponds to incidence of one new case of hypopituitarism per 15 patient-years. Age, gender, tumor function, tumor volume, suprasellar extension, prescription dose of radiation, as well as dose-volume to the pituitary gland, stalk and hypothalamus were not predictive factors for the development of hypopituitarism. CONCLUSIONS: In our cohort of patients with pituitary tumors who underwent GKRS, 30% developed new hypopituitarism during the follow-up period.

Serial Re-Expansion of Pituitary Gland Is Associated with Endocrinologic Recovery.

BACKGROUND: Minimizing pituitary dysfunction by preservation of the normal pituitary gland has a significant clinical impact on patient outcome after pituitary surgery. This study aimed to determine whether re-expansion of the healthy gland after surgery was related to endocrinologic outcome. METHODS: From January 2012 to July 2014, 112 patients were eligible for this retrospective study. Magnetic resonance imaging with dynamic contrast enhancement done2 days and 3 months before and after surgery was evaluated to assess the tumor and normal pituitary gland. We assessed the size of the pituitary gland and evaluated the relationship with endocrinologic outcome. RESULTS: The mean preoperative size of the gland was 3.86 mm, within 2 days after surgery it was 5.50 mm and 3 months after surgery it was 7.17 mm. Preoperatively patients were grouped based on their requirement of hormone replacement. Patients who required hormone replacement therapy before surgery and did not recover from hormonal insufficiency were classified as group 1 (26 patients), those who recovered from preoperative hormonal insufficiency and discontinued hormone replacement after surgery were classified as group 2 (17 patients), and those who showed hormonally normal status and did not need hormone replacement before and after surgery were in group 3 (68 patients). In group 1, the size of the gland expanded 1.24 times within postoperative 2 days but had no increase after 3 months (1.25 mm) (P = 0.716). Group 2 showed a 1.30 times larger gland within postoperative 2 days and 2.37 times at 3 months follow-up (P = 0.001). Group 3 showed 1.62 times larger gland at postoperative day 2 and 2.1 times larger at the 3-month follow-up. CONCLUSIONS: Serial re-expansion of the healthy pituitary gland at the 3-month follow-up magnetic resonance imaging can predict the endocrinologic recovery.

Improved versus worsened endocrine function after transsphenoidal surgery for nonfunctional pituitary adenomas: rate, time course, and radiological analysis.

OBJECTIVE: The impact of transsphenoidal surgery for nonfunctional pituitary adenomas (NFAs) on preoperative hypopituitarism relative to the incidence of new postoperative endocrine deficits remains unclear. The authors investigated rates of hypopituitarism resolution and development after transsphenoidal surgery. METHODS: Over a 5-year period, 305 transsphenoidal surgeries for NFAs performed at The California Center for Pituitary Disorders were retrospectively reviewed. RESULTS: Patients with preoperative endocrine deficits (n = 153, 50%) were significantly older (mean age 60 vs 54 years; p = 0.004), more frequently male (65% vs 44%; p = 0.0005), and had larger adenomas (2.4 cm vs 2.1 cm; p = 0.02) than patients without preoperative deficits (n = 152, 50%). Of patients with preoperative endocrine deficits, 53% exhibited symptoms. Preoperative deficit rates were 26% for the thyroid axis; 20% and 16% for the male and female reproductive axes, respectively; 13% for the adrenocorticotropic hormone (ACTH)/cortisol axis, and 19% for the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. Laboratory normalization rates 6 weeks and 6 months after surgery without hormone replacement were 26% and 36% for male and 13% and 13% for female reproductive axes, respectively; 30% and 49% for the thyroid axis; 3% and 3% for the cortisol axis; and 9% and 22% for the IGF-1 axis (p < 0.05). New postoperative endocrine deficits occurred in 42 patients (13.7%). Rates of new deficits by axes were: male reproductive 3% (n = 9), female reproductive 1% (n = 4), thyroid axis 3% (n = 10), cortisol axis 6% (n = 19), and GH/IGF-1 axis 4% (n = 12). Patients who failed to exhibit any endocrine normalization had lower preoperative gland volumes than those who did not (0.24 cm(3) vs 0.43 cm(3), respectively; p < 0.05). Multivariate analyses revealed that no variables predicted new postoperative deficits or normalization of the female reproductive, cortisol, and IGF-1 axes. However, increased preoperative gland volume and younger age predicted the chances of a patient with any preoperative deficit experiencing normalization of at least 1 axis. Younger age and less severe preoperative hormonal deficit predicted normalization of the thyroid and male reproductive axes (p < 0.05). CONCLUSIONS: After NFA resection, endocrine normalization rates in this study varied with the hormonal axis and were greater than the incidence of new endocrine deficits. Low preoperative gland volume precluded recovery. Patient age and the severity of the deficiency influenced the recovery of the thyroid and male reproductive axes, the most commonly impaired axes and most likely to normalize postoperatively. This information can be of use in counseling patients with hypopituitarism who undergo NFA surgery.

Inflammation and oxidative stress in viper bite: an insight within and beyond.

Though systemic and local manifestations of snakebite are considered serious, the relevance of oxidative stress in viper bite pathology is largely denied. However, over the past decade, studies have provided substantial evidence for the presence of persistent oxidative stress in viper bite victims. This review aims at highlighting the disturbances in redox homeostasis soon after viper envenomation and its implications in the pathomechanism of secondary/long term complications including thrombocytopenia, hypopituitarism, infertility, renal abnormalities and persistent local tissue degradation. Both enzymatic and non-enzymatic components of viper venom play a pivotal role in bringing redox turbulence in victims. Venom-induced hemorrhage and necrosis with subsequent release of damage associated molecular pattern (DAMPs) molecules also contribute to sustained oxidative stress and inflammation. Studies have demonstrated that along with anti-venom therapy an antioxidant treatment during the early stages of viper bite and also long term treatment could help to reduce the occurrence of secondary/long term complications. Further, proper knowledge regarding the pathophysiology will allow for exploration of new avenues in the treatment of viper bite.

Radiotherapy-induced hypopituitarism: a review.

Hypopituitarism is a disorder caused by impaired hormonal secretions from the hypothalamic-pituitary axis. Radiotherapy is the most common cause of iatrogenic hypopituitarism. The hypothalamic-pituitary axis inadvertently gets irradiated in patients receiving prophylactic cranial radiotherapy for leukemia, total body irradiation and radiotherapy for intracranial, base skull, sinonasal and nasopharyngeal tumors. Radiation-induced hypopituitarism (RIH) is insidious, progressive and largely nonreversible. Mostly, RIH involves one hypothalamic-pituitary axis; however, multiple hormonal axes deficiency starts developing at higher doses. Although the clinical effects of the hypopituitarism are more profound in children and young adults, its implications in older adults are being increasingly recognized. The risk continues to persist or increase up to 10 years following radiation exposure. The clinical management of hypopituitarism is challenging both for the patients and healthcare providers. Here we have reviewed the scale of the problem, the risk factors and the management of RIH.

Optimal surgical approaches for Rathke cleft cyst with consideration of endocrine function.

BACKGROUND: Surgical indications for Rathke cleft cyst are not clear. OBJECTIVE: To evaluate postoperative outcomes in terms of endocrine function. METHODS: The study analyzed a total 73 patients who underwent transsphenoidal surgery. All patients underwent a visual field test, combined pituitary function test, and magnetic resonance imaging before and after surgery. A follow-up combined pituitary function test was performed at 1.5-year intervals. RESULTS: The mean age at the time of surgery was 35 ± 14 years, and the male/female ratio was 1:1.25 (33/40). The mean follow-up duration after surgery was 59 ± 39 months. The most common symptoms were headache (84%), visual disturbance (48%), and polyuria (38%). After transsphenoidal surgery, 75% of polyuria and 96% of visual field defects were resolved, and pituitary function improved in 42% of patients. The mean age of patients who exhibited worsened hypopituitarism was significantly higher than that of patients who exhibited unchanged or improved hypopituitarism (44 ± 15.7 vs 33 ± 13.5 years; P = .02). Twelve patients (16%) experienced recollection of cyst, but none required reoperation. Five of the recollected cysts presented with characteristics that were different from those of the initial lesions, and 2 recollected cysts underwent spontaneous regression. CONCLUSION: Minimal incision with radical removal of cyst content is reasonable to prevent the development of endocrine disturbances and other complications. Individualized risks and benefits must be assessed before a decision is reached regarding surgery and surgical method. Patients with recurrent Rathke cleft cyst require careful follow-up with special attention rather than a hasty operation.

Does pituitary radiotherapy increase the risk of stroke and, if so, what preventative actions should be taken?

Radiotherapy for pituitary adenomas is a well-established and effective treatment, but it has been linked to a number of complications, including an increased risk of cerebrovascular disease and mortality. Possible underlying mechanisms include the direct effects of radiation on cerebral vasculature and deficiencies in specific pituitary hormones. Higher administered dose of radiotherapy is one of the main predictors of stroke. Although treatment strategies for stroke prevention in patients treated with pituitary radiotherapy have not been studied, using the lowest effective radiation dose and ensuring hormone deficiencies are adequately treated may be beneficial in reducing the risk of stroke.

Combined simultaneous transcranial and transsphenoidal resection of large-to-giant pituitary adenomas.

BACKGROUND: While large-to-giant pituitary adenomas (PAs) may be safely removed by experienced surgeons through a single route, the procedure is technically challenging. We present the outcome of a simultaneous combined transcranial and transsphenoidal approach and discuss its applications. METHODS: A retrospective review was conducted on 12 consecutive patients. Surgical complications, visual and endocrinological functions, and tumour control were reviewed. RESULTS: There were four men and eight women, with a mean age of 47.6 years. All but one patient had non-functioning PAs. The mean tumour height was 4.1 cm (range: 2.3-5.5). The predominant presenting symptoms were visual field loss in eight patients, headache in three patients and mental confusion in one patient. There was no operative mortality. Post-operative cerebrospinal fluid leakage occurred in one patient. Five of the eight patients who presented with visual field loss achieved full recovery, and three had partial improvement. Two patients developed permanent diabetes insipidus after surgery. Panhypopituitarism occurred in one patient. Gross total removal (GTR) was achieved in five, and subtotal removal (STR) in seven patients. Seven patients received post-operative external irradiation. All patients who had GTR remained tumour-free and all those with STR had stable diseases after a mean follow-up period of 53.1 months (range: 14.1-92.1). CONCLUSION: The simultaneous 'above and below' approach is a safe and effective surgical strategy for large-to-giant PAs, particularly when expertise in endoscopic transsphenoidal surgery is unavailable. Its use, however, should be limited to a carefully selected group of patients, and tailored to individual user's expertise and experience.

Factors associated with endocrine deficits after stereotactic radiosurgery of pituitary adenomas.

OBJECTIVE: To analyze the factors associated with anterior pituitary deficits after pituitary adenoma stereotactic radiosurgery (SRS). METHODS: The tumor, pituitary stalk, and pituitary gland were segmented on the dose plans of 82 patients (secreting tumors, n = 53; nonsecreting tumors, n=29) for dose-volume analysis. No patient had undergone prior radiation therapy and all patients had at least 12 months of endocrinological follow-up (median, 63 months; mean, 69 months; range, 13-134). RESULTS: Thirty-four patients (41%) developed new anterior pituitary deficits at a median of 32 months (range, 2-118) after SRS. The risk of developing new anterior pituitary deficits was 16% and 45% at 2 and 5 years, respectively. Multivariate analysis of the entire group showed that poor visualization of the pituitary gland (hazard ratio [HR]=2.63, 95% confidence interval [CI]=1.10-6.25, P=.03) was associated with a higher rate of new anterior pituitary deficits. Dosimetric analysis of 60 patients whose pituitary gland could be clearly identified showed that increasing mean pituitary gland radiation dose correlated with new anterior pituitary deficits (HR=1.11, 95% CI=1.02-1.20, P=.02). New anterior pituitary deficits stratified by mean pituitary gland radiation dose: 19.1 Gy, 83% (5/6). CONCLUSION: New endocrine deficits after pituitary adenoma radiosurgery were correlated with increasing radiation dose to the pituitary gland. Methods that limit the radiation dose to the pituitary gland during SRS may increase the probability of preserving pituitary function.

Neurorehabilitation in traumatic brain injury: does it make a difference?

Each year, 1.4 million people in the United States are seen in a hospital for a traumatic brain injury. Those with moderate-to-severe traumatic brain injury frequently go through a course of inpatient neurorehabilitation prior to discharge back into the community. A broad overview of neurorehabilitation is presented, including the standards for admission to inpatient rehabilitation and the members and roles of the neurorehabilitation team. Common medical complications that are managed after moderate-to-severe traumatic brain injury are reviewed. The spectrum of arousal issues is summarized. The evidence regarding neurorehabilitation is then reviewed. Future studies that are underway to better understand the utility of neurorehabilitation are then discussed.

Gamma knife stereotactic radiosurgery of Nelson syndrome.

OBJECTIVE: Gamma knife radiosurgery (GKR) can be used as primary or adjuvant therapy for the treatment of an ACTH-producing pituitary tumor after bilateral adrenalectomy, called Nelson syndrome (NS). We have examined the effect of GKR on tumor growth and ACTH-hypersecretion, and characterized the adverse events of this treatment in patients with NS. DESIGN: Cross-sectional follow-up study. First, retrospective data pre- and post-GKR were collected. Patients then underwent a predefined survey including radiological, endocrinological, ophthalmological, and neurosurgical evaluation. SUBJECTS: Ten patients treated with GKR for NS after previous bilateral adrenalectomy. The mean follow-up was 7 years. No patient was lost to follow-up. RESULTS: Tumor growth was stopped in all patients. The ACTH levels declined in eight patients, and normalized in one patient. There was a significant drop in ACTH levels, with a half-time of 2.8 years. No patient developed visual field defects or any other cranial nerve dysfunction as a result of treatment. Four patients started hormone substitution therapy during the follow-up period. The substitution therapy of three pituitary axes present at GKR treatment could be stopped during the same period. One patient developed a glioblastoma in the left parieto-occipital region 14 years after GKR, far from the field of treatment. As the radiation level was below 1Gy to this area, it is unlikely that the GKR treatment itself induced the malignant tumor. CONCLUSION: In patients with NS, GKR is an effective adjuvant treatment, carrying relatively few adverse effects. Although the risk of developing a secondary neoplasia after GKR is present, it is probably extremely low.

Hypopituitary control and complications study (HypoCCS): a decade of an outcomes assessment observational study.

The Hypopituitary Control and Complications Study (HypoCCS) was set up in 1995 to monitor the long-term efficacy of GH replacement therapy in adult patients with GH deficiency (GHD). The key findings to date have focussed on the diagnosis of GHD, the effects of GH on lean body mass, lipids and bone, and the quality of life benefits. Current guidelines recommend that the diagnosis of adult GHD be proven biochemically. However, these tests are not suitable for all patients, and data from this study suggest that the presence of 3 or more pituitary hormone defects can predict adult GHD with 95% accuracy. The 3-yr efficacy analysis showed that GH replacement therapy in adults is effective in improving body composition, bone mass and lipid profiles, but age is an important factor in determining the response to treatment. Quality of life was improved and maintained during long-term GH replacement therapy in adults. Future results will show if these initial benefits have been sustained.

Efficacy of current growth hormone treatments and future therapies.

Despite huge advances having been made in some areas of medicine, options for the treatment of GH deficiency (GHD) have remained constant since the introduction of GH in the 1950s. Several initiatives have been introduced to improve the understanding and treatment of GHD with GH, including the long-term Hypopituitary Control and Complications Study (HypoCCS) and the issuance of clinical guidelines. This article considers the impact of these initiatives and considers new treatment options which will potentially provide important future benefits for GHD patients.

[Pituitary and adrenal gland surgery]. / Hypophysen- und Nebennierenoperationen.

Laparoscopic adrenalectomy and transsphenoidal pituitary surgery are currently established as the surgical procedures of choice with a low complication rate. Beyond potential surgical complications, one has to consider endocrine sequelae such as adrenal insufficiency and hypopituitarism. Without adequate endocrine treatment patients are prone to develop potentially lethal complications such as Addisonian crises or pituitary coma. Therefore, all patients should be seen by an endocrinologist before and after surgery. Patients with bilateral adrenalectomy require lifelong substitution of glucocorticoids and mineralocorticoids. Cushing's syndrome patients with unilateral adrenalectomy need temporary substitution. After pituitary surgery, all patients require functional assessment of their pituitary function, and, if necessary, adequate replacement therapy.

[Growth hormone therapy in adults]. / Wachstumshormontherapie beim Erwachsenen.

In adult patients with growth hormone deficiency due to organic hypopituitarism, substitution with growth hormone is very useful and well established. Positive influence on numerous target parameters has been investigated in randomised controlled trials (evidence level I) and could be documented. Thus, growth hormone substitution in hypopituitarism is scientifically founded and has been admitted by the authorities in the European Union. Concerning pharmacotherapy with growth hormone in healthy elderly persons without pituitary disease and also doping in sports, the situation is completely different. Use of growth hormone in these circumstances has not sufficiently been investigated concerning indications, efficacy and safety. Ethical and economical aspects have not been evaluated yet. Serious concerns about the therapeutic safety need to be considered.

Treatment of patients with a pituitary adenoma: one clinician's experience.

The diagnosis and treatment of a patient with a pituitary adenoma or another type of pituitary lesion requires a team approach involving the neurosurgeon, endocrinologist, primary care physician, and, in some patients, an ophthalmologist and radiation therapist. The diagnosis of excessive pituitary hormone secretion and/or loss of pituitary function is based on biochemical findings and can usually be confirmed by performing blood tests, except for patients with suspected Cushing syndrome. The primary treatment of pituitary adenomas is resection, except in patients with a prolactin-producing tumor, who are most successfully treated medically with a dopamine agonist. In this article the author reviews the principles of diagnosis and treatments and offers recommendations for ideal patient care.

Mortality, cardiovascular events and risk factors in hypopituitarism.

The issue of whether hypopituitarism is a risk factor for increased mortality from all causes, and particularly from vascular disease, has been evaluated in four retrospective analyses. In all studies, all-cause mortality was significantly increased by 1.3-2.2-fold compared to age- and sex-matched cohorts. The increase in vascular mortality was significant in the two studies from Sweden (1.8-1.9-fold) but not in the two from the UK (0.8-1.4-fold). The total number of deaths relating to all-cause and vascular mortality was relatively small, and the 95% confidence intervals on the observed to expected (O/E) mortality ratios were wide, in some instances crossing the unity line. As retrospective epidemiological studies, these trials suffer from several drawbacks. They included small numbers of patients and events (i.e. deaths), and determination of the number of deaths and their causes may be incomplete, with small additions or subtractions impacting on O/E mortality ratios. A precise diagnosis of pituitary hormone deficiency in patients recruited in the earlier years of the studies (pre-1965) often relied on historical details and not on firm biochemical values. None of the studies provided any measurement of growth hormone status for the cohorts, and in only one study was there any relationship between a particular axis deficiency and all-cause mortality. This finding suggested that hypogonadal subjects were relatively protected compared with eugonadal counterparts. However, this must be regarded as a preliminary conclusion. These retrospective studies indicate that there are no data to support a relationship between vascular or all-cause mortality in hypopituitarism and growth hormone deficiency. Nevertheless, they do provide preliminary evidence to suggest that it would be worthwhile to conduct a large, multicentre, prospective study of well-characterized and documented patients with a sufficient number of events, in order to establish definitively the relationship between various axis deficiencies and mortality.

Pituitary function in patients with Rathke's cleft cyst: significance of surgical management.

The pituitary function of patients with Rathke's cleft cyst before and after surgery was investigated to clarify the significance of surgery and operative indications. The authors have treated 19 patients with Rathke's cleft cyst. There were panhypopituitarism in 2 patients (11%), amenorrhea and/or galactorrhea in 3 (16%), diabetes insipidus in 4 (21%), and visual disturbance in 9 (47%). All the patients underwent systematic endocrinological examination and were found to have various degrees of pituitary dysfunction. Panhypopituitarism was endocrinologically confirmed in 2 patients. Hyperprolactinemia was observed in 4. These patients underwent aspiration of the cyst contents and biopsy of the cyst wall. Postoperative follow-up endocrinologic evaluation performed more than 3 months after surgery showed improvement in pituitary function in 9 out of 13 patients (69%). Amenorrhea and/or galactorrhea recovered or improved in 100% of patients and visual disturbance improved in 89%. However, diabetes insipidus and panhypopituitarism did not improve postoperatively, in any patient. The results of the present study indicate that the incidence of pituitary dysfunction in patients with Rathke's cleft cyst is higher than suspected and in most cases surgical intervention improves pituitary function and the clinical status of the patient. Therefore, surgical treatment is recommended even when the patient has only mild symptoms or signs, including pituitary dysfunction, to prevent irreversible panhypopituitarism.