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Hypophysitis is defined as inflammation of the pituitary gland. It is a heterogeneous condition as it can originate from different parts of the pituitary gland, can be caused by different pathophysiological processes, and can be isolated or the manifestation of a underlying systemic disease. Hypophysitis usually presents with endocrine deficiencies, including diabetes insipidus, with varying patterns. A subset of patients presents with mass effects. The last decades major progress has been made in the understanding of this disease. New forms are now recognized, new diagnostics are being developed, and specific treatments are proposed. This review provides an overview of the current knowledge on hypophysitis using an aetiology-based approach and provides the clinician with a stepwise approach to the patient with (suspected) hypophysitis. (C) 2021 Published by Elsevier Masson SAS.

Introduction The extended endoscopic approach (EEA) provides direct access for resection of tuberculum sellae (TSM) and olfactory groove meningiomas (OGM) but is associated with cerebrospinal fluid (CSF) leak in up to 25% of patients. To evaluate the impact of improved skull base reconstructive techniques, we assessed published CSF leak percentages in EEA over the last two decades. Method Random-effects meta-analyses were performed for studies published between 2004-2020. Outcomes assessed were CSF leak, gross total resection, visual improvement, intraoperative arterial injury and 30-day mortality. For the main analyses, publications were pragmatically grouped based on publication year in three categories: 2004-2010, 2011-2015, and 2016-2020. Results We included 29 studies describing 540 TSM and 115 OGM patients. CSF leak incidence dropped over time from 22% (95% CI: 6-43%) in studies published between 2004 and 2010, to 16% (95% CI: 11-23%) between 2011 and 2015, and 4% (95% CI: 1-9%) between 2016 and 2020. Outcomes of gross total resection, visual improvement, intraoperative arterial injury, and 30-day mortality remained stable over time Conclusions We report a noticeable decrease in CSF leak over time, which might be attributed to the development of reconstructive techniques (e.g., hadad bassagasteguy flap, and gasket seal), refined multilayer repair protocols, and selected lumbar drain usage.

Objective: Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) excess results in both reversible and irreversible musculoskeletal damage, including increased vertebral fracture (VF) risk. The prevalence of VFs is approximately 60% in controlled acromegaly patients, and these VFs can progress in time. We aimed to identify the course of VFs in a cohort of acromegaly patients in long-term remission and their associated risk factors during prolonged follow-up. Methods: Thirty-one patients with acromegaly (49% female, median age 60 years (IQR 53–66)), who were in remission for ≥2 years, were included in this longitudinal, prospective, follow-up study. Spine radiographs of vertebrae Th4 to L4 were assessed for VFs using the Genant score, at baseline, after 2.6 years and 9.1 years. Progression was defined as either a new fracture or a ≥1-point increase in Genant score. Results: The prevalence of VF at baseline was 87% (27/31 patients). Progression of VFs was observed in eleven patients (35.5%) during the 9.1-year follow-up period, with a total incidence rate of 65.5 per 1000 person years (males 59.8 per 1000 person years vs females 71.6 per 1000 person years). Patients treated with surgery or radiotherapy had a higher risk of VF progression in this cohort (P = 0.030). Conclusions: In this cohort of long-term, well-controlled acromegalic patients, the prevalence and progression of VFs was high, showing that the deleterious effects of GH and IGF-1 excess on bone persist despite achievement of longstanding remission.

Background: Among chordoma patients, recurrent cases are by far more complex to be managed, and cranio-cervical junction (CCJ) localizations represent a particular challenge due to the complexity of the anatomical egion which makes it difficult to obtain a radical resection.Methodology: We report our personal experience in treating four patients with recurrent CCJ chordoma with "personalized" multiportal and eventually multistage approaches.Conclusions: Endoscopic endonasal approaches have gained widespread acceptance and are considered the workhorse in most cases of craniocervical junction chordomas. Nonetheless, in some cases of recurrence, or in presence of very lateralized lesions/ anatomical variations midline approaches are either contraindicated or very difficult to perform. In all these cases it seems reasonable to consider a versatile strategy including different approaches, modulating the surgical needs with different answers and solutions offered by the different routes. In other words to personalize as much as possible the approach, being creative and not dogmatic.

Background: Surgical innovation is different from the introduction of novel pharmaceuticals. To help address this, in 2009 the IDEAL Collaboration (Idea, Development, Exploration, Assessment, Long-term follow-up) introduced the five-stage framework for surgical innovation. To evaluate the framework feasibility for novel neurosurgical procedure introduction, two innovative surgical procedures were examined: the endoscopic endonasal approach for skull base meningiomas (EEMS) and the WovenEndobridge (WEB device) for endovascular treatment of intracranial aneurysms. Methods: The published literature on EEMS and WEB devices was systematically reviewed. Identified studies were classified according to the IDEAL framework stage. Next, studies were evaluated for possible categorization according to the IDEAL framework. Results: Five hundred seventy-six papers describing EEMS were identified of which 26 papers were included. No prospective studies were identified, and no studies reported on ethical approval or patient informed consent for the innovative procedure. Therefore, no clinical studies could be categorized according to the IDEAL Framework. For WEB devices, 6229 articles were screened of which 21 were included. In contrast to EEMS, two studies were categorized as 2a and two as 2b. Conclusion: The results of this systematic review demonstrate that both EEMS and WEB devices were not introduced according to the (later developed in the case of EEMS) IDEAL framework. Elements of the framework such as informed consent, ethical approval, and rigorous outcomes reporting are important and could serve to improve the quality of neurosurgical research. Alternative study designs and the use of big data could be useful modifications of the IDEAL framework for innovation in neurosurgery.

Objective: To assess the quality of life (QOL) impact of extended endonasal approaches and nasoseptal flap reconstruction for benign skull base tumours Methods: A random sample of 110 patients undergoing either limited endonasal transphenoidal hypophysectomy or extended endonasal approaches (trans-cribriform, trans-sellar, trans-tuberculum, trans-pterygoid) for the removal of benign skull base tumours were asked to complete Rhinosinusitis Outcome Measure (RSOM-31) questionnaire. Results: A total of 91 patients returned the completed questionnaire. All patients in the limited approach group had pituitary adenomas, while patients in the extended group had a variety of tumours including adenomas with suprasellar or cavernous extension, chordomas, meningiomas, craniopharyngiomas and dermoids. Median time to completion of questionnaire was 1104 days in the limited group and 142 days in the extended approaches group. Although smell and headache were significantly worse in the group undergoing reconstruction with Haddad flap, there was no significant difference in overall, nasal, general, emotional or sleep quality of life between the two groups. Both smell and headache showed significant improvement with time. In linear regression, the single most important factor independently associated with overall worse RSOM-31 total scores was the presence of secreting adenomas. Conclusion: The use of nasoseptal flap appears to have a limited negative impact in nasal quality of life, mainly related to heada- che and reduced smell, both of which tend to improve with time. Hormone-secreting tumours have the most important adverse effect in quality of life extending in general, emotional, sleep and overall wellbeing, as reflected in RSOM 31 subscales.

BACKGROUND: Meningioma are common benign intracranial tumours, that can cause severe neurological and daily functional problems, sometimes requiring lifelong care and support. Current practice and guidelines lack focus on these long-term sequelae. Value-Based Healthcare (VBHC) initiatives aim to increase the value of care for patients, but continuous evaluation and improvement of these initiatives is required. According to the Plan-Do-Study-Act (PDSA) cycle, a model for continuous healthcare evaluation and improvement, we explored issues in meningioma care trajectories, possible high impact initiatives to improve these issues, and the implementability of these initiatives. MATERIAL AND METHODS: Previously, issues in the meningioma care trajectories were identified through a survey by The Netherlands Comprehensive Cancer Organisation. Using a grounded theory approach, a thematic framework was constructed based on this data and used for further data collection through three semi-structured interviews with patient-partner dyads (i.e. pairs) and four focus groups with patient-partner dyads and healthcare providers (both two focus groups). RESULTS: Issues in meningioma care trajectories reported by patient-partner dyads and healthcare providers were related to information, care and support, logistics, and diagnostics and treatment. Most important issues were lack of information about intervention and outcomes, and lack of support after treatment. A reported solution for many issues was the incorporation of a case manager. Other possible solutions were implementation of routine use of patient-reported outcome measures (PROMs) or a rehabilitation program, and formalization of these care trajectories. The most important barriers for these solutions were budget, capacity, ICT infrastructure, qualified personnel, and know-how. CONCLUSION: Implementation of a few simple solutions (e.g. case manager) may improve the majority of experienced issues in meningioma care trajectories. Information on the identified barriers and facilitators can be used to ensure successful implementation of these practice changing initiatives, which need iterative evaluation in PDSA cycles.

Background Angiogenesis inhibition is a rational treatment strategy for high-grade glioma (HGG). Combined antiangiogenic therapy and chemotherapy could be beneficial, taking advantage of different mechanisms of antitumour activity of both therapies. We carried out a phase I–II clinical trial with the combination of bevacizumab and continuous dose-intense temozolomide (TMZ) for patients with a recurrent HGG after first- or second-line treatment. Patients and methods Twenty-three HGG patients were treated with bevacizumab (10 mg/kg i.v. every 3 weeks) and TMZ (daily 50 mg/m2), until clinical or radiological progression. Conventional and dynamic magnetic resonance imaging (MRI) were carried out on days -4, 3 and 21 and until clinical or radiological progression. Results Overall response rate (20%), 6-month progression-free survival (PFS6) (17.4%), median progression-free survival (13.9 weeks) and median overall survival (OS) (17.1 weeks) were considerably lower compared with most other studies with bevacizumab-containing regimens. The dynamic MRI parameters contrast transfer coefficient and relative cerebral blood volume decreased rapidly during the early phases of treatment, reflecting changes in vascularisation and vessel permeability but not in tumour activity. In addition, >50% of patients showed oedema reduction and a reduced shift on T1 images. Conclusion Treatment with bevacizumab and TMZ is feasible and well tolerated but did not improve PFS6 and median OS.

Ieder jaar wordt in Nederland bij zeven- a achthonderd patienten een goedaardige tumor van het centraal zenuwstelsel vastgesteld. Het aantal langdurige overlevers is een veelvoud daarvan. Ondanks de goede genezingskansen houden veel patienten (15-50%) blijvend neurologische en psychosociale beperkingen ten gevolge van de aandoening en/of de behandeling.

Cerebellar haemorrhage is an unusual complication of supratentorial neurosurgery. Several causative pre-operative factors and medical risk factors may predispose patients to cerebellar haemorrhage, however its etiology remains still unclear. Only two case reports have previously described the occurrence of cerebellar haemorrhage after subdural haematoma evacuation by burr-hole trepanation. We present two patients with this rare postoperative complication of minor supratentorial neurosurgery and possible underlying pathophysiological mechanisms are discussed. Our two cases support the post- rather than per-operative pathogenetic hypothesis. Although the complication is associated with a significant morbidity and mortality, most cases follow a benign course.

Level-changing behavior is a form of anticipatory behavior of a male rat, when tested in a bilevel testbox. The male explores the testcage prior to introduction of a female. The female is introduced after 5 min. The number of level changes displayed by the male in this period reflects appetitive aspects of sexual behavior and it was suggested that analysis of this level-changing behavior may function as assessment of sexual motivation. In this study the increase of anticipatory level changes over repeated weekly tests was dependent upon (sexual) olfactory stimulation. The number of anticipatory level changes was reliably reduced by administration of the opioid antagonist naloxone, suggesting that endogenous opioids facilitate this behavior. These results suggest that the increase of anticipatory level changes over repeated tests is a response to olfactory stimuli and reflects appetitive aspects of sexual behavior, which are stimulated by endogenous opioids. These results are in accordance with the concept that analysis of anticipatory level-changing behavior can be used to assess sexual motivation.

In recent years much has become known about the substrates in the brain involved in the regulation of masculine sexual behavior and the involvement of specific neurochemicals in these brain areas. In the present paper the experimental data concerning the involvement of a number of brain areas in sexual behavior are reviewed, in relation to an incentive motivational theory of sexual behavior. The review is restricted to the involvement of opioids and dopamine, of which the role in sexual motivation and behavior is best documented. Opioids in the medial preoptic area (mPOA) impair sexual performance, although the endogenous opioids systems may be quiescent in normal, sexually active rats. Dopamine in the mPOA has a facilitative role in the masculine sexual performance. The corticomedial amygdala is involved in processing of sensory information, especially olfactory stimuli, which are subsequently directed towards the mPOA. Local β-endorphin infusion interferes with this processing. Endogenous opioids in the ventral tegmental area activate the mesoaccumbens dopamine system and stimulate the sexual motivation. Increased dopamine transmission in the nucleus accumbens correlates with increased sexual motivation and vice versa. The basolateral amygdala plays an essential role in the association of environmental stimuli with reward and therefore in the expression of conditioned sexual motivation. Finally, the reviewed data are integrated and a comprehensive view on the relations between various neural substrates is composed.

Background:A vast number of generic and disease specific questionnaires are used to measure health-related quality of life (HRQoL) in meningioma research. We aimed to assess the relevance of issues mentioned in these questionnaires and to compare the patient’s perspective with the perspective of the health care professional (HCP) on meningioma-related symptoms and problems.Methods:A systematic literature search was conducted to identify all HRQoL items and questionnaires. Both patients and HCPs had to rate the relevance of each item on a 4-point Likert scale (ranging from ‘not at all’ to ‘very much’): items were relevant when ≥ 30% of patients or HCPs scored the items as relevant. For each questionnaire the percentage of relevant items was assessed. All identified items were categorized into different domains of HRQoL, which were discussed in semi-structured interviews with both groups. The aim of these interviews was to reveal all issues of meningioma patients, including issues not present in the existing questionnaires.Results:Included in this study were 14 patients (mean age 56 years, 71% female) and 7 HCPs (2 neurosurgeons, 2 neurologists, 2 radiotherapists, 1 rehabilitation specialist, mean experience 15 years). Fourteen different questionnaires were found in the literature, including 140 unique issues. Patients and HCPs considered 25–60% and 90–100% of the items of each questionnaire as relevant, respectively. When comparing the 12 most relevant issues as assessed by meningioma patients and HCPs, only 5 issues were the same. Issues missing in the already existing questionnaires were mostly issues in the psychological and cognitive domains (e.g. multitasking and stress-management).Conclusion:Existing HRQoL questionnaires do not fully cover the problems of meningioma patients. Patients and HCPs differ in opinion what the most relevant issues are of meningioma patients. Both findings support the need to develop and validate an HRQoL questionnaire specific for meningioma patients.

The sexual activity of 40 male Wistar rats was tested weekly in a bilevel test chamber to evaluate the involvement of endogenous opioids in the appetitive and consummatory aspects of sexual behavior. It has been suggested that the increase of the anticipatory level-changing behavior over repeated testing, displayed before the introduction of a receptive female, is sexually motivated. Two doses of the opioid antagonist naloxone, 1 and 10 mg/kg, prevented the increase of the anticipatory level-changing over four repeated tests of sexually experienced rats without prior experience in the bilevel test chamber and decreased the number of level changes of rats displaying a high number of level changes. Analysis of the pattern of inhibition suggested that the lower dose of naloxone may reduce sexual reward and that, in addition, the higher dose may block the expression of motivation. In contrast, naloxone treatment facilitated the efficiency of the sexual performance, with less mounts and intromissions preceding ejaculation and a shorter ejaculation latency, implying an inhibitory role of endogenous opioids in the neural control of some aspects of sexual performance (e.g., ejaculatory threshold). These results suggest that endogenous opioids may increase sexual appetite and diminish sexual performance.

Primary brain tumours are relatively rare, but brain metastases are a frequent complication of the most common cancers elsewhere in the body (breast, lung, melanoma). Loss of function and excitation of brain nerves i.e. sensory loss, paralysis and pain in the head-and-neck region are specific features in base of skull tumours: meningioma, glomus tumours, vestibular Schwannoma, meningeal metastases by breast cancer, melanoma, and leukaemia, melanoma. In the diagnosis and treatment of brain tumours, special attention is required for rare complications in the head and neck region.

Objective: Postoperative radiotherapy is standard treatment for patients with a glioblastoma multiforme (GBM). However, a GBM is radioresistant and almost always recurs, even after a high dose of radiation. A GBM is characterized by its extensive neo-angiogenesis, which can be attributed to the high levels of vascular endothelial growth factor (VEGF). The scope of this study is to investigate the VEGF secretion by GBM cells with different radiosensitivity after irradiation. Methods:Three human GBM cell lines (U251, U251-NG2 and U87) were irradiated with single doses of 0, 5, 10 and 20 Gy of gamma(3)-rays from a Cs-137 source. VEGF levels in medium were measured by ELISA at 24, 48 and 72 h after radiation. Cell survival was measured by the XTT assay 7 days after irradiation. Results:Following single dose radiation, the VEGF levels showed a dose dependent increase in U251, U251-NG2 and U87 glioma cells. Both base-line and radiation-enhanced VEGF levels were about 10-fold higher in U87 compared to U251 and U251-NG2 cells. In addition, in the XTT assay, the U87 was more radioresistant than both U251 and U251-NG2 cell lines (dose modifying factor (DMF) = 1.6 and 1.7 resp). Conclusion:Irradiation enhanced VEGF secretion in all three tested glioma cell lines (up to eight times basal levels). It is tempting to associate the radiation-enhanced VEGF secretion with an increased angiogenic potential of the tumor, which may be a factor in radioresistance

Anticipatory level-changing behavior is a form of appetitive sexual behavior displayed by male rats prior to introduction of a female in a bilevel testbox. Analysis of this level-changing behavior may serve as assessment of sexual motivation. Because ejaculation affects appetitive aspects of sexual behavior, measures purporting to assess sexual motivation should be effected by ejaculation. We observed that ejaculation prior to testing reduced the number of anticipatory level changes of a male rat. This reduction was greater when tested after two than after one ejaculation. Our results support the concept that analysis of anticipatory level-changing behavior can be used to measure sexual motivation.

The sexual motivation and performance of male rats were observed in a bilevel testing chamber after bilateral infusion of 40 pmol beta-endorphin, 2.75 nmol naloxone or saline into the ventral tegmental area for four succeeding, weekly tests. In the 5 min prior to introduction of the female rat, the male rat explores the bilevel testing chamber. It was previously shown that the increase over tests of these anticipatory level changes is sexually motivated and a response to olfactory stimuli. Naloxone infusion into the VTA prevented the increase of anticipatory level changes. beta-Endorphin failed to affect the anticipatory level-changing behavior. The sexual performance was unaffected by naloxone or beta-endorphin treatment, but the number of ejaculating rats decreased with repeated testing after naloxone treatment. It is concluded that endogenous opioid systems in the ventral tegmental area contribute to the stimulation of sexual motivation and/or reward, presumably by stimulating the mesolimbic dopamine system in response to sex-related olfactory stimuli.

Local infusion of beta-endorphin (beta-END) into the medial preoptic area (MPOA) dose-dependently impaired the gating of the copulatory response and the execution of the sexual performance of sexually experienced, intact male rats. Local naloxone treatment prevented the impairment of the sexual response by beta-END, but failed to facilitate unimpaired copulation. Local infusion into the MPOA of equimolar doses of alpha-endorphin, dynorphin-A-(1-17) or met-enkephalin were less effective than beta-END. It is suggested that endogenous opioid systems in the MPOA are normally quiescent, and increased activity may be related to disrupted or inhibited male sexual behavior.