Towards a pituitary apoplexy classification based on clinical presentation and patient journey.

PURPOSE: The condition of pituitary apoplexia contains the clinical spectre from life-threatening emergency to asymptomatic self-limiting course, which partly determines diagnostic delay and management. Outcome evaluation of course and management of pituitary apoplexia is hampered by the diverse presentation of this condition and requires appraisal. This study aimed to describe the patient journey, clinical presentation, and management of various types of pituitary apoplexy in a new classification to facilitate future outcome evaluation and identify unmet needs in the care process. METHODS: A single-center retrospective patient chart study was conducted between 2005-2021 (N = 98). Outcome measures were clinical symptoms at first presentation in hospital, being headache, consciousness, visual acuity, visual field defects (VFD), ophthalmoplegia, nausea, vomiting, fever, and hypopituitarism and care process characteristics. RESULTS: Mean age was 47.6 ± 16.6 years (51.0% male). We describe their patient journey and identified three different types, differing in clinical presentation, in-hospital route, and final treatment, e.g., Acute (type A, 52%), Subacute (type B, 22.5%), and Non-acute (type C, 25.5%). Type A generally presents with acute onset headaches, VFD, or ophthalmoplegia emergency setting, with lowest mean visual acuity of both eyes and frequent hypocortisolism. CONCLUSIONS: Pituitary apoplexy can be approached as a spectrum of disease with 3 main subtypes, with a different initial presentation, different in-hospital route resulting in different management. Acknowledging subtypes with particular needs for (emergency) referrals to Pituitary Tumors Center of Excellence (PTCOE) will serve patient care improvements, outcome evaluations and address areas for improvement.

Hypophysitis: A comprehensive overview.

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.

Progression of vertebral fractures in long-term controlled acromegaly: a 9-year follow-up study.

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.

Innovation in neurosurgery: less than IDEAL? A systematic review.

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.

Bevacizumab and dose-intense temozolomide in recurrent high-grade glioma.

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/m(2)), 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.

[Diagnosis and treatment of brain tumours]. / Diagnose en behandeling van hersentumoren.

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.

[Subtle skin lesions in the midline as an indication of a neurodermal closing defect]. / Subtiele huidafwijkingen in de mediaanlijn als aanduiding van een neurodermaal sluitingsdefect.

Three patients, aged 2, 2.5 and 24 years, presented with a skin lesion in the median or paramedian area at the nose, in the lumbar region and between the shoulders, respectively. The first patient suffered from recurrent infection, the skin lesion of the second patient was a coincidental finding, and the third patient had cosmetic problems. Although there were no signs of neurological deficits, neurodermal closing defects were found by MRI. Two patients underwent surgery to prevent infection and neurological complaints in the future. It is stressed that even if there are no neurological signs or infections, congenital dermal lesions situated in the midline should be considered as possible neural tube defects and therefore analysed by MRI. Ifa neurodermal dysraphism is found, patients should be referred to a neurosurgical centre. A good clinical assessment of the neural lesion, clinical signs and age will determine whether surgical resection is indicated to prevent or resolve neurological problems, infections or cosmetic complaints.

Cerebellar haemorrhage after non-traumatic evacuation of supratentorial chronic subdural haematoma: report of two cases.

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.

Radiation-enhanced vascular endothelial growth factor (VEGF) secretion in glioblastoma multiforme cell lines--a clue to radioresistance?

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-rays from a (137)Cs 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.

Endogenous opioids and reward.

The discovery of endogenous opioids has markedly influenced the research on the biology of addiction and reward brain processes. Evidence has been presented that these brain substances modulate brain stimulation reward, self-administration of different drugs of abuse, sexual behaviour and social behaviour. There appears to be two different domains in which endogenous opioids, present in separate and distinct brain regions, are involved. One is related to the modulation of incentive motivational processes and the other to the performance of certain behaviours. It is concluded that endogenous opioids may play a role in the vulnerability to certain diseases, such as addiction and autism, but also when the disease is present, such as alcoholism.

Appetitive sexual behavior in male rats: 1. The role of olfaction in level-changing behavior.

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.

Appetitive sexual behavior in male rats: 2. sexual reward and level-changing behavior.

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.

Sexual motivation: involvement of endogenous opioids in the ventral tegmental area.

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.

Regulation of masculine sexual behavior: involvement of brain opioids and dopamine.

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 beta-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.

Opioids and sexual behavior of male rats: involvement of the medial preoptic area.

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.

Endogenous opioids and sexual motivation and performance during the light phase of the diurnal cycle.

The sexual motivation and performance of sexually experienced male rats were tested during the light phase of the diurnal cycle after treatment with saline or 1 mg.kg-1 naloxone in a bilevel testing box. The sexual motivation during the light phase, as assessed by the increase in anticipatory level changes prior to introduction of a receptive female on subsequent weekly sessions, was comparable to that during the dark phase. Opioid blockade reduced the increase of level changes, suggesting that endogenous opioids are involved in sexual motivation. The sexual performance was impaired during the light phase. Naloxone treatment failed to affect the sexual performance, other than that the post ejaculatory refractory period was increased. This increased latency to re-initiate copulation may be an expression of the reduced sexual motivation. It is concluded that endogenous opioids are not involved in the regulation of the impaired sexual performance during the light phase of the diurnal cycle. In contrast, the sexual motivation, which displays no marked diurnal variation, may be stimulated by endogenous opioids.

Endogenous opioids are differentially involved in appetitive and consummatory aspects of sexual behavior of male rats.

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.

The grasping response in rats: interaction between gamma-type endorphins and haloperidol.

gamma-Type endorphins mimic neuroleptics in inducing a grasping response in rats. It was studied whether the haloperidol-induced grasping response was altered after blockade of gamma-type endorphin activity in the rat brain. To achieve this blockade rats were injected i.c.v. with gamma-endorphin antiserum or with a monoclonal anti-idiotype desenkephalin-gamma-endorphin antibody, which may bio-inactivate the gamma-type endorphins or block the putative receptors for gamma-type endorphins, respectively. The results showed that both treatments attenuated the haloperidol-induced grasping response, particularly 3 h after haloperidol treatment. The influence of these antibodies appeared to be specific, since other sera were without effect. Thus there may be an interaction between the endogenous gamma-type endorphin activity and the haloperidol-induced grasping response.