Controlled Study of Pre- and Postoperative Headache in Patients with Sellar Masses (HEADs-uP Study).

INTRODUCTION: Sellar masses are common intracranial neoplasms. Their clinical manifestations vary widely and include headache. We aimed to determine whether the prevalence and characteristics of headache in patients with sellar tumours differ from the general population and to investigate the effect of tumour resection on this complaint. METHODS: We performed a prospective, controlled study in a single tertiary centre and included 57 patients that underwent transsphenoidal resection for a sellar mass (53% females, mean age 53.5 ± 16.4) and 29 of their partners (controls; 45% females, mean age 54.8 ± 14.9). Outcome measures were prevalence, characteristics and impact of headache 1 month preoperatively and at neurosurgical follow-up 3 months postoperatively. RESULTS: Preoperatively, the prevalence of regular headache (≥1 time per month) was higher in patients than in controls (54% vs. 17%, p < 0.001), and patients scored higher on headache impact questionnaires (all p ≤ 0.01). At postoperative follow-up, headache prevalence decreased in both groups, but the decrease in regular headache frequency and impact was larger in patients than in controls, and no between-group differences remained. CONCLUSIONS: More than half of patients with sellar tumours suffer from at least once-monthly headaches, and both regular headache occurrence and impact are higher compared with controls. The more pronounced decrease in headache complaints in patients versus controls at postoperative follow-up suggests an additional effect of tumour resection next to the factor time.

Lanreotide versus placebo for tumour reduction in patients with a 68Ga-DOTATATE PET-positive, clinically non-functioning pituitary macroadenoma (GALANT study): a randomised, multicentre, phase 3 trial with blinded outcome assessment.

Background: No established medical treatment options currently exist for patients with non-functioning pituitary macroadenoma (NFPMA). Somatostatin analogues may prevent tumour growth, but randomised controlled trials are lacking. In vivo somatostatin receptor assessment with 68Ga-DOTATATE PET could help in selecting patients for treatment. We aimed to determine the effect of the somatostatin analogue lanreotide on tumour size in patients with a 68Ga-DOTATATE PET-positive NFPMA. Methods: The GALANT study was an investigator-initiated, multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial with recruitment at three academic hospitals in the Netherlands. Adult patients with a suprasellar extending NFPMA, either surgery-naïve or postoperative remnant ≥10 mm, were eligible for inclusion. Important exclusion criteria were previous sellar radiotherapy and use of dopamine receptor agonists. Somatostatin receptor expression in the NFPMA was determined through 68Ga-DOTATATE PET/CT, co-registered with MRI. A predefined sample of 44 patients with PET-positive NFPMA were randomly assigned (1:1) to lanreotide acetate 120 mg or placebo, both administered as deep subcutaneous injections every 28 days for 72 weeks. Primary outcome was the change in cranio-caudal tumour diameter measured on pituitary MRI from baseline to end-of-treatment in the intention-to-treat population. Participants, investigators and outcome assessors were masked to treatment allocation. The trial is registered with the Netherlands Trial Registry, NL5136, and EudraCT, 2015-001234-22. Findings: Between Nov 3, 2015, and Dec 10, 2019, 49 patients were included in the study. Forty-four patients with a 68Ga-DOTATATE PET-positive NFPMA were randomly assigned to lanreotide (22 [50%]) or placebo (22 [50%]). Study treatment was completed in 13 (59%) lanreotide and 19 (86%) placebo participants. The mean (SD) change from baseline in cranio-caudal tumour diameter after treatment was +1·2 (2·5) mm with lanreotide and +1·3 (1·5) mm with placebo; adjusted mean difference versus placebo -0·1 mm (95% CI -1·3 to 1·2, p = 0·93). Adverse events occurred in 22 (100%, 147 events) lanreotide and 21 (95%, 94 events) placebo participants. Gastrointestinal complaints were most common, reported by 18 (82%) lanreotide and 8 (36%) placebo participants. There were no treatment-related serious adverse events. Interpretation: Compared with placebo, lanreotide treatment did not reduce tumour size or growth in patients with 68Ga-DOTATATE PET-positive NFPMA. Funding: Ipsen Farmaceutica BV.

Basal cortisol in relation to metyrapone confirmation in predicting adrenal insufficiency after pituitary surgery.

PURPOSE: Pituitary surgery can lead to post-surgical adrenal insufficiency with the need for glucocorticoid replacement and significant disease related burden. In patients who do not receive hydrocortisone replacement before surgery, at our center, an early morning plasma cortisol concentration using a cut-off value of 450 nmol/L 3 days after surgery (POD3) is used to guide the need for hydrocortisone replacement until dynamic confirmatory testing using metyrapone. The aim of this study was to critically assess the currently used diagnostic and treatment algorithm in patients undergoing pituitary surgery in our pituitary reference center. METHODS: Retrospective analysis of all patients with a POD3 plasma cortisol concentration < 450 nmol/L who received hydrocortisone replacement and a metyrapone test after 3 months. Plasma cortisol concentration was measured using an electrochemiluminescence immunoassay (Roche). All patients who underwent postoperative testing using metyrapone at Amsterdam UMC between January 2018 and February 2022 were included. Patients with Cushing's disease or those with hydrocortisone replacement prior to surgery were excluded. RESULTS: Ninety-five patients were included in the analysis. The postoperative cortisol concentration above which no patient had adrenal insufficiency (i.e. 11-deoxycortisol > 200 nmol/L) was 357 nmol/L (Sensitivity 100%, Specificity 31%, PPV:32%, NPV:100%). This translates into a 28% reduction in the need for hydrocortisone replacement compared with the presently used cortisol cut-off value of 450 nmol/L. CONCLUSION: Early morning plasma cortisol cut-off values lower than 450 nmol/L can safely be used to guide the need for hydrocortisone replacement after pituitary surgery.

Continuing Challenges in the Definitive Diagnosis of Cushing's Disease: A Structured Review Focusing on Molecular Imaging and a Proposal for Diagnostic Work-Up.

The definitive diagnosis of Cushing's disease (CD) in the presence of pituitary microadenoma remains a continuous challenge. Novel available pituitary imaging techniques are emerging. This study aimed to provide a structured analysis of the diagnostic accuracy as well as the clinical use of molecular imaging in patients with ACTH-dependent Cushing's syndrome (CS). We also discuss the role of multidisciplinary counseling in decision making. Additionally, we propose a complementary diagnostic algorithm for both de novo and recurrent or persistent CD. A structured literature search was conducted and two illustrative CD cases discussed at our Pituitary Center are presented. A total of 14 CD (n = 201) and 30 ectopic CS (n = 301) articles were included. MRI was negative or inconclusive in a quarter of CD patients. 11C-Met showed higher pituitary adenoma detection than 18F-FDG PET-CT (87% versus 49%). Up to 100% detection rates were found for 18F-FET, 68Ga-DOTA-TATE, and 68Ga-DOTA-CRH, but were based on single studies. The use of molecular imaging modalities in the detection of pituitary microadenoma in ACTH-dependent CS is of added and complementary value, serving as one of the available tools in the diagnostic work-up. In selected CD cases, it seems justified to even refrain from IPSS.

The added value of cerebrospinal fluid analysis in patients with subarachnoid hemorrhage after negative noncontrast CT.

OBJECTIVE: In patients presenting within 6 hours after signs and symptoms of suspected subarachnoid hemorrhage (SAH), CSF examination is judged to be no longer necessary if a noncontrast CT (NCCT) scan rules out SAH. In this study, the authors evaluated the performance of NCCT to rule out SAH in patients with positive CSF findings. METHODS: Between January 2006 and April 2018, 1657 patients were admitted with a nontraumatic SAH. Of these patients, 1546 had positive SAH findings on the initial NCCT and 111 patients had an NCCT scan that was reported as negative in the acute setting, but with positive CSF examination for subarachnoid blood. Demographic data, World Federation of Neurosurgical Societies grade, and SAH time points (ictus, time of NCCT, and time of lumbar puncture) were collected. All 111 NCCT scans were reevaluated by an experienced neuroradiologist. RESULTS: Of the 111 patients with positive CSF findings, SAH was initially missed on NCCT in 25 patients (23%). Reevaluation of 21 patients presenting within 6 hours of symptom onset confirmed NCCT negative findings in 12 (5 aneurysms), an aneurysmal SAH (aSAH) pattern in 8 (7 aneurysms), and a perimesencephalic pattern in 1 patient. Reevaluation of 90 patients presenting after 6 hours confirmed negative NCCT findings in 74 patients (37 aneurysms), aSAH pattern in 10 (4 aneurysms), and a perimesencephalic pattern in 6 (2 aneurysms). CONCLUSIONS: CSF examination is still mandatory to rule out SAH as NCCT can fail to show blood, even within 6 hours after symptom onset. In addition, the diagnosis SAH was frequently missed during initial reporting.

The GALANT trial: study protocol of a randomised placebo-controlled trial in patients with a 68Ga -DOTATATE PET-positive, clinically non-functioning pituitary macroadenoma on the effect of lan reotide on t umour size.

INTRODUCTION: At present, there is no approved medical treatment option for patients with non-functioning pituitary adenoma. A number of open-label studies suggest that treatment with somatostatin analogues may prevent tumour progression. In vivo somatostatin receptor imaging using 68Ga-DOTATATE PET (PET, positron emission tomography) could help in preselecting patients potentially responsive to treatment. Our aim is to investigate the effect of the somatostatin analogue lanreotide as compared with placebo on tumour size in patients with a 68Ga-DOTATATE PET-positive non-functioning pituitary macroadenoma (NFMA). METHODS AND ANALYSIS: The GALANT study is a multicentre, randomised, double-blind, placebo-controlled trial in adult patients with a suprasellar extending NFMA. Included patients undergo a 68Ga-DOTATATE PET/CT of the head and tracer uptake is assessed after coregistration with pituitary MRI. Forty-four patients with a 68Ga-DOTATATE PET-positive NFMA are randomised in a 1:1 ratio between lanreotide 120 mg or placebo, both administered as subcutaneous injections every 28 days for 72 weeks. The primary outcome is the change in cranio-caudal tumour diameter on pituitary MRI after treatment. Secondary outcomes are change in tumour volume, time to tumour progression, change in quality of life and number of adverse events. Final results are expected in the second half of 2021. ETHICS AND DISSEMINATION: The study protocol has been approved by the Medical Research Ethics Committee of the Academic Medical Centre (AMC) of the Amsterdam University Medical Centres and by the Dutch competent authority. It is an investigator-initiated study with financial support by Ipsen Farmaceutica BV. The AMC, as sponsor, remains owner of all data. Results will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NL5136 (Netherlands Trial Register); pre-recruitment.

Complications in cranioplasty after decompressive craniectomy: timing of the intervention.

OBJECTIVE: To prevent complications following decompressive craniectomy (DC), such as sinking skin flap syndrome, studies suggested early cranioplasty (CP). However, several groups reported higher complication rates in early CP. We studied the clinical characteristics associated with complications in patients undergoing CP, with special emphasis on timing. METHODS: A single-center observational cohort study was performed, including all patients undergoing CP from 2006 to 2018, to identify predictors of complications. RESULTS: 145 patients underwent CP: complications occurred in 33 (23%): 18 (12%) epi/subdural hemorrhage, 10 (7%) bone flap infection, 4 (3%) hygroma requiring drainage, and 1 (1%) post-CP hydrocephalus. On univariate analysis, acute subdural hematoma as etiology of DC, symptomatic cerebrospinal fluid (CSF) flow disturbance (hydrocephalus) prior to CP, and CP within three months after DC were associated with higher complication rates. On multivariate analysis, only acute subdural hematoma as etiology of DC (OR 7.5; 95% CI 1.9-29.5) and symptomatic CSF flow disturbance prior to CP (OR 2.9; 95% CI 1.1-7.9) were associated with higher complication rates. CP performed within three months after DC was not (OR 1.4; 95% CI 0.5-3.9). Pre-CP symptomatic CSF flow disturbance was the only variable associated with the occurrence of epi/subdural hemorrhage. (OR 3.8; 95% CI 1.6-9.0) CONCLUSION: Cranioplasty has high complication rates, 23% in our cohort. Contrary to recent systematic reviews, early CP was associated with more complications (41%), explained by the higher incidence of pre-CP CSF flow disturbance and acute subdural hematoma as etiology of DC. CP in such patients should therefore be performed with highest caution.

Why Do Patients with Poor-Grade Subarachnoid Hemorrhage Die?

BACKGROUND: Poor-grade subarachnoid hemorrhage (SAH) has been associated with a high case fatality, either in the acute phase or in the later stages. The exact causes of death in these patients are unknown. METHODS: We performed a retrospective study of all consecutive patients with SAH with World Federation of Neurosurgical Societies grade IV or V on admission from 2009 to 2013 at 2 tertiary referral centers in Amsterdam, the Netherlands, and Toronto, Ontario, Canada, who had died during their hospital stay. RESULTS: Of 357 patients, 152 (43%) had died. Of these 152 patients, 87 (24%) had not undergone aneurysm treatment. The median interval to death was 3 days (interquartile range, 1-12 days) after initial hemorrhage. The major cause of death in both centers was withdrawal of life support (107 patients [71%]; 74 of 94 [79%] in Amsterdam and 33 of 58 [58%] in Toronto; P < 0.01), followed by brain death in 23 (15%; 16 of 58 [28%] in Amsterdam vs. 7 of 94 [7%] in Toronto; P < 0.01). The remaining causes of death represented <15%. CONCLUSIONS: The decision to withdraw life support was the major reason for death of patients with poor-grade SAH for an overwhelming majority of the patients. The exact reasons for withdrawal of life support, other than cultural and referral differences, were undetermined. Insight into the reasons of death should be prospectively studied to improve the care and clinical outcomes of patients with poor-grade SAH.

Early Treatment Decisions in Poor-Grade Patients with Subarachnoid Hemorrhage.

BACKGROUND: Patients with World Federation of Neurosurgical Societies (WFNS) grade V subarachnoid hemorrhage (SAH) mostly have a poor outcome. Correct identification of patients who might benefit from treatment remains challenging. We investigated which disease-related characteristics, present at admission, could identify patients with chance of good outcome. METHODS: In total, 146 consecutive patients with WFNS grade V SAH (2002-2013) were included. Demographic and disease-related characteristics were compared between patients with a good outcome (Glasgow Outcome Scale 4 and 5) and a poor outcome (Glasgow Outcome Scale 1-3). Subgroups were made of patients with aneurysm treatment according to outcome; 1) good outcome; 2) poor outcome, with optimal general treatment; and 3) poor outcome, general treatment discontinued. RESULTS: In total, 34 of the 146 patients had a good outcome (36% of all treated patients); 16 (47%) of these presented with a Glasgow Coma Scale score of 3, versus 65 (58%) of patients with a poor outcome (P = 0.33). Eleven (33%) patients in the good outcome group presented with pupillary abnormalities; 4 (12%) even had bilaterally fixed and dilated pupils, versus 49 (46%) in patients with a poor outcome (P < 0.01). In 51 patients, the aneurysm was not treated; all died. CONCLUSIONS: More than one third of all treated patients with WFNS grade V SAH had a good outcome. All patients in whom the aneurysm was not treated died. Reliable identification of patients who will reach good outcome, on the basis of symptoms on admission, seems impossible, as these symptoms are not discriminating enough.

Time intervals from aneurysmal subarachnoid hemorrhage to treatment and factors contributing to delay.

In the management of aneurysmal subarachnoid hemorrhage (aSAH), aneurysm treatment as early as feasible is mandatory to minimize the risk of a rebleed and may thus improve outcome. We assessed the different time intervals from the first symptoms of aSAH to start of aneurysm treatment in an effort to identify which factors contribute mostly to a delay in time to treatment. In 278 aSAH patients, time intervals between the different steps from initial hemorrhage to aneurysm treatment were retrospectively reviewed, and delaying factors were determined. Half of the patients presented to a hospital within 115 min (IQR 60-431). The median (IQR) interval from hemorrhage to diagnosis was 169 min (96-513), and from diagnosis to treatment 1,057 min (416-1,428), or 17.6 h. Aneurysm treatment started within 24 h in 76 % of treated patients. Independent factors predicting delay to treatment were primary presentation at a referring hospital and admission to the treatment center later in the day. Delay in treatment was not independently related to poor outcome. The interval to aneurysm treatment might be improved upon by immediate and direct transport to the treatment center combined with optimization of in-hospital logistics, following the 'time-is-brain' concept so successfully adopted in the treatment of ischemic stroke.