Endoscopic transsphenoidal resection of parasellar abducens nerve schwannoma: A video demonstration.

Background: The abducens nerve schwannoma (ANS) in the sellar and parasellar region are extremely rare. Only around two dozen of ANS have been described in the world literature. These cases were, however, operated through the transcranial approach. We demonstrate, with the help of an edited video, that ANS located in the sellar and parasellar region can be safely and effectively operated through a transsphenoidal approach under endoscopic visualization. Case Description: Here, we present a case of a 30-year-old male who presented with a nine-month history of diplopia, weight gain, and loss of sexual functions. On neuro-opthalmological examination, a mild abducens palsy on the left side. Other cranial nerves were intact. On endocrinological testing, mild hypopituitarism on gonadal and thyroid axes. Magnetic resonance imaging (MRI) scan showed a contrast-enhanced cystic lesion in the sellar and parasellar region extending into the left temporal fossa. The patient underwent endonasal transsphenoidal endoscopic resection. A binostril standard approach was used, the left middle concha resected, and the nasoseptal flap was raised [Video 1]. The tumor was relatively soft and avascular yet invasive and could be removed with straight and curved suctions and gentle curettage. Subcapsular dissection was the key to saving the sixth nerve. Only minimal remnant posterior to the left internal carotid artery was assumed to be left behind. No cerebrospinal fluid (CSF) leakage was noted during the surgery. The skull base defect was reconstructed with the left-sided nasoseptal flap [Video 1]. Postoperatively, no new cranial nerve deficits. Diplopia is preoperative. Endocrine functions were unchanged. No CSF leak was observed. Postoperative MRI scan showed a near total resection. There was no operation-relevant complication. Diplopia resolved completely in a follow-up period of 6 months. Conclusion: The endoscopic transsphenoidal route is safe and effective for the resection of parasellar ANS. Subcapsular dissection is key to keep the sixth nerve intact.

Functional hemispheric disconnection procedures for chronic epilepsy: history, indications, techniques, complications and current practice in Europe. A consensus statement on behalf of the EANS functional neurosurgery section.

Introduction: The surgical procedure for severe, drug-resistant, unilateral hemispheric epilepsy is challenging. Over the last decades the surgical landscape for hemispheric disconnection procedures changed from anatomical hemispherectomy to functional hemispherotomy with a reduction of complications and stable good seizure outcome. Here, a task force of European epilepsy surgeons prepared, on behalf of the EANS Section for Functional Neurosurgery, a consensus statement on different aspects of the hemispheric disconnection procedure. Research question: To determine history, indication, timing, techniques, complications and current practice in Europe for hemispheric disconnection procedures in drug-resistant epilepsy. Material and methods: Relevant literature on the topic was collected by a literature search based on the PRISMA 2020 guidelines. Results: A comprehensive overview on the historical development of hemispheric disconnection procedures for epilepsy is presented, while discussing indications, timing, surgical techniques and complications. Current practice for this procedure in European epilepsy surgery centers is provided. At present, our knowledge of long-term seizure outcomes primarily stems from open surgical disconnection procedures. Although minimal invasive surgical techniques in epilepsy are rapidly developing and reported in case reports or small case series, long-term seizure outcome remain uncertain and needs to be reported. Discussion and conclusion: This is the first paper presenting a European consensus statement regarding history, indications, techniques and complications of hemispheric disconnection procedures for different causes of chronic, drug-resistant epilepsy. Furthermore, it serves as the pioneering document to report a comprehensive overview of the current surgical practices regarding this type of surgery employed in renowned epilepsy surgery centers across Europe.

Type one chiari malformation as a cause of central sleep apnea and hypoventilation in children.

OBJECTIVES: Chiari type 1 malformation (CM1) may occasionally lead to central sleep apnea (CSA). We studied, in a large clinical cohort of pediatric CM1 patients, the effect of CM1 on breathing during sleep. METHODS: This is a retrospective single pediatric pulmonology center study with a systematic evaluation of pediatric CM1 patients under age 18 with polysomnography (PSG) during 2008-2020. Children with syndromes were excluded. All patients had undergone head and spine magnetic resonance imaging. RESULTS: We included 104 children with CM1 with a median age of 7 (interquartile range (IQR) 5-13) years. The median extent of tonsillar descent (TD) was 13 (IQR 10-18) mm. Syringomyelia was present in 19 children (18%). Of all children, 53 (51%) had normal PSG, 35 (34%) showed periodic breathing or central apnea and hypopnea index ≥5 h-1, and 16 (15%) displayed features of compensated central hypoventilation and end-tidal or transcutaneous carbon dioxide 99th percentile level above 50 mmHg. TD had the best predictive value for central breathing disorders. In a linear model, both age (61%) and TD (39%) predicted median breathing frequency (R = 0.33, p < 0.001). CONCLUSIONS: Although severe CSA is a rare complication of brainstem compression in pediatric patients with CM1, short arousal-triggered episodes of periodic breathing and mild compensated central hypoventilation are common. TD shows the best but still poor prediction of the presence of a central breathing disorder. This highlights the use of PSG in patient evaluation. Posterior fossa decompression surgery effectively treats central breathing disorders.

One-year costs of intensive care in pediatric patients with traumatic brain injury.

OBJECTIVE: Traumatic brain injury (TBI) is a major cause of death and disability in the pediatric population. The authors assessed 1-year costs of intensive care in pediatric TBI patients. METHODS: In this retrospective multicenter cohort study of four academic ICUs in Finland, the authors used the Finnish Intensive Care Consortium database to identify children aged 0-17 years treated for TBI in ICUs between 2003 and 2013. The authors reviewed all patient health records and head CT scans for admission, treatment, and follow-up data. Patient outcomes included functional outcome (favorable outcome defined as a Glasgow Outcome Scale score of 4-5) and death within 6 months. Costs included those for the index hospitalization, rehabilitation, and social security up to 1 year after injury. To assess costs, the authors calculated the effective cost per favorable outcome (ECPFO). RESULTS: In total, 293 patients were included, of whom 61% had moderate to severe TBI (Glasgow Coma Scale [GCS] score 3-12) and 40% were ≥ 13 years of age. Of all patients, 82% had a favorable outcome and 9% died within 6 months of injury. The mean cost per patient was €48,719 ($54,557) (95% CI €41,326-€56,112). The index hospitalization accounted for 66%, rehabilitation costs for 27%, and social security costs for 7% of total healthcare costs. The ECPFO was €59,727 ($66,884) (95% CI €52,335-€67,120). A higher ECPFO was observed among patients with clinical and treatment-related variables indicative of parenchymal swelling and high intracranial pressure. Lower ECPFO was observed among patients with higher admission GCS scores and those who had epidural hematomas. CONCLUSIONS: Greater injury severity increases ECPFO and is associated with higher postdischarge costs in pediatric TBI patients. In this pediatric cohort, over two-thirds of all resources were spent on patients with favorable functional outcome, indicating appropriate resource allocation.

Psychotropic Medication After Intensive Care Unit-Treated Pediatric Traumatic Brain Injury.

BACKGROUND: Our aim was to assess the occurrence and risk factors for psychotropic medication use after pediatric traumatic brain injury treated in the intensive care unit. METHODS: We combined data from the Finnish Intensive Care Consortium database, data on reimbursed medications from the Social Insurance Institute, and individual electronic health care data. We analyzed data on children aged five to 17 years treated for traumatic brain injury in intensive care units of four university hospitals in Finland during 2003 to 2013 and being alive six months after injury with no history of psychotropic medication use before traumatic brain injury. RESULTS: We identified 248 patients of whom 46 (19%) were prescribed a new psychotropic medication after traumatic brain injury. In multivariable logistic regression, a higher age associated with a higher probability for use of any psychotropic medication. Subgroup analyses showed that higher age associated with an increased risk of antidepressant and antipsychotic use but with a decreased risk of stimulant use. Apart from age, we found no other clinical, radiological, or treatment-related factors that significantly associated with subsequent use of psychotropics. Psychotropic medication was most common (45%) in children aged 12 to 17 years and had moderate disability at six-month follow-up. CONCLUSIONS: One fifth of children treated in the intensive care unit for traumatic brain injury were prescribed a new psychotropic medication during a median follow-up of three years and five months. Psychotropic medication was most common among teenagers with moderate post-traumatic disability. The need and use of psychotropics postinjury seem multifactorial and not related to any traumatic brain injury type.

Surgical treatment of a rare rosette-forming glioneuronal tumor in the pineal region.

BACKGROUND: Rosette-forming glioneuronal tumors (RGNTs) in the pineal region are rare. RGNTs have been described in the fourth ventricle, but rarely reported in other brain regions. Here, we report the radiological findings, surgical treatment, and short-term outcome of an RGNT found in the pineal region. CASE DESCRIPTION: We present a case of a 22-year-old medical student with a 4-month history of headaches and diplopia. A previous magnetic resonance imaging scan revealed a mass in the pineal region, with heterogeneous contrast enhancement and hydrocephalus. Three months prior, an endoscopic biopsy and third ventriculocisternostomy were performed elsewhere; the diagnosis was neurocytoma Grade I, and radiotherapy was planned. The patient presented at our hospital for a second opinion, and we suggested surgical treatment. A near-total resection was performed in sitting position using a supracerebellar infratentorial microsurgical approach. The tumor was very soft and not well vascularized. Diplopia was initially worsened after the tumor was removed and relieved completely after 2 weeks. An 8-week follow-up examination revealed that the patient was free of symptoms. Histological analysis confirmed it was an RGNT. CONCLUSION: Maximal safe resection in pineal region RGNTs is a feasible and recommended treatment option.

Posttraumatic epilepsy in intensive care unit-treated pediatric traumatic brain injury patients.

OBJECTIVE: Posttraumatic epilepsy (PTE) is a well-described complication of traumatic brain injury (TBI). The majority of the available data regarding PTE stem from the adult population. Our aim was to identify the clinical and radiological risk factors associated with PTE in a pediatric TBI population treated in an intensive care unit (ICU). METHODS: We used the Finnish Intensive Care Consortium database to identify pediatric (<18 years) TBI patients treated in four academic university hospital ICUs in Finland between 2003 and 2013. Our primary outcome was the development of PTE, defined as the need for oral antiepileptic medication in patients alive at 6 months. We assessed the risk factors associated with PTE using multivariable logistic regression modeling. RESULTS: Of the 290 patients included in the study, 59 (20%) developed PTE. Median age was 15 years (interquartile range [IQR] 13-17), and 80% had an admission Glasgow Coma Scale (GCS) score ≤12. Major risk factors for developing PTE were age (adjusted odds ratio [OR] 1.08, 95% confidence interval [CI] 1.00-1.16), obliterated suprasellar cisterns (OR 6.53, 95% CI 1.95-21.81), and an admission GCS score of 9-12 in comparison to a GCS score of 13-15 (OR 2.88, 95% CI 1.24-6.69). SIGNIFICANCE: We showed that PTE is a common long-term complication after ICU-treated pediatric TBI. Higher age, moderate injury severity, obliterated suprasellar cisterns, seizures during ICU stay, and surgical treatment are associated with an increased risk of PTE. Further studies are needed to identify strategies to decrease the risk of PTE.

Comparison of Black Bone MRI and 3D-CT in the preoperative evaluation of patients with craniosynostosis.

PURPOSE: Black Bone (BB) magnetic resonance imaging (MRI) is a nonionizing imaging method and a recent alternative to computed tomography (CT) in the examination of cranial deformities. The purpose of this study was to compare BB-MRI and routine 3D-CT in the preoperative evaluation of patients with craniosynostosis. METHODS: At our center, we have routinely performed preoperative CT of the skull and brain MRI for patients with clinical suspicion of craniosynostosis. We recently changed our MRI protocol into one that includes sequences for the evaluation of both brain anatomy and skull bone and sutures by BB-MRI. A semi-automatic skull segmentation algorithm was developed to facilitate visualization. Both BB-MRI and 3D-CT were performed on 9 patients with clinical craniosynostosis, and the images were evaluated by two craniofacial surgeons, one pediatric neurosurgeon, and two neuroradiologists. RESULTS: We obtained informative 3D images using BB-MRI. Six (6/9) patients had scaphocephaly, 1 (1/9) patient had unicoronal synostosis, and 2 (2/9) patients had lambdoid synostosis. The affected synostotic sutures could be identified both by BB-MRI and by 3D-CT in all patients. Intra-rater and inter-rater reliability for rating the calvarial sutures was high. However, the reliability for rating the intracranial impressions was low by both imaging methods. CONCLUSION: BB-MRI is an alternative to 3D-CT in the preoperative evaluation of patients with craniosynostosis. BB-MRI provides information not only on cranial sutures and intracranial impressions but also on the brain structure in one imaging session. This method can replace ionizing radiation-based methods in analyzing skull deformities.

Trends in pediatric epilepsy surgery in Europe between 2008 and 2015: Country-, center-, and age-specific variation.

OBJECTIVE: To profile European trends in pediatric epilepsy surgery (<16 years of age) between 2008 and 2015. METHODS: We collected information on volumes and types of surgery, pathology, and seizure outcome from 20 recognized epilepsy surgery reference centers in 10 European countries. RESULTS: We analyzed retrospective aggregate data on 1859 operations. The proportion of surgeries significantly increased over time (P < .0001). Engel class I outcome was achieved in 69.3% of children, with no significant improvement between 2008 and 2015. The proportion of histopathological findings consistent with glial scars significantly increased between the ages of 7 and 16 years (P for trend = .0033), whereas that of the remaining pathologies did not vary across ages. A significant increase in unilobar extratemporal surgeries (P for trend = .0047) and a significant decrease in unilobar temporal surgeries (P for trend = .0030) were observed between 2008 and 2015. Conversely, the proportion of multilobar surgeries and unrevealing magnetic resonance imaging cases remained unchanged. Invasive investigations significantly increased, especially stereo-electroencephalography. We found different trends comparing centers starting their activity in the 1990s to those whose programs were developed in the past decade. Multivariate analysis revealed a significant variability of the proportion of the different pathologies and surgical approaches across countries, centers, and age groups between 2008 and 2015. SIGNIFICANCE: Between 2008 and 2015, we observed a significant increase in the volume of pediatric epilepsy surgeries, stability in the proportion of Engel class I outcomes, and a modest increment in complexity of the procedures.

Genetic and Epigenetic Characterization of Growth Hormone-Secreting Pituitary Tumors.

Somatic driver mechanisms of pituitary adenoma pathogenesis have remained incompletely characterized; apart from mutations in the stimulatory Gα protein (Gαs encoded by GNAS) causing activated cAMP synthesis, pathogenic variants are rarely found in growth hormone-secreting pituitary tumors (somatotropinomas). The purpose of the current work was to clarify how genetic and epigenetic alterations contribute to the development of somatotropinomas by conducting an integrated copy number alteration, whole-genome and bisulfite sequencing, and transcriptome analysis of 21 tumors. Somatic mutation burden was low, but somatotropinomas formed two subtypes associated with distinct aneuploidy rates and unique transcription profiles. Tumors with recurrent chromosome aneuploidy (CA) were GNAS mutation negative (Gsp- ). The chromosome stable (CS) -group contained Gsp+ somatotropinomas and two totally aneuploidy-free Gsp- tumors. Genes related to the mitotic G1-S-checkpoint transition were differentially expressed in CA- and CS-tumors, indicating difference in mitotic progression. Also, pituitary tumor transforming gene 1 (PTTG1), a regulator of sister chromatid segregation, showed abundant expression in CA-tumors. Moreover, somatotropinomas displayed distinct Gsp genotype-specific methylation profiles and expression quantitative methylation (eQTM) analysis revealed that inhibitory Gα (Gαi) signaling is activated in Gsp+ tumors. These findings suggest that aneuploidy through modulated driver pathways may be a causative mechanism for tumorigenesis in Gsp- somatotropinomas, whereas Gsp+ tumors with constitutively activated cAMP synthesis seem to be characterized by DNA methylation activated Gαi signaling. IMPLICATIONS: These findings provide valuable new information about subtype-specific pituitary tumorigenesis and may help to elucidate the mechanisms of aneuploidy also in other tumor types.

Validation of prognostic models in intensive care unit-treated pediatric traumatic brain injury patients.

OBJECTIVE: There are few specific prognostic models specifically developed for the pediatric traumatic brain injury (TBI) population. In the present study, the authors tested the predictive performance of existing prognostic tools, originally developed for the adult TBI population, in pediatric TBI patients requiring stays in the ICU. METHODS: The authors used the Finnish Intensive Care Consortium database to identify pediatric patients (< 18 years of age) treated in 4 academic ICUs in Finland between 2003 and 2013. They tested the predictive performance of 4 classification systems-the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) TBI model, the Helsinki CT score, the Rotterdam CT score, and the Marshall CT classification-by assessing the area under the receiver operating characteristic curve (AUC) and the explanatory variation (pseudo-R2 statistic). The primary outcome was 6-month functional outcome (favorable outcome defined as a Glasgow Outcome Scale score of 4-5). RESULTS: Overall, 341 patients (median age 14 years) were included; of these, 291 patients had primary head CT scans available. The IMPACT core-based model showed an AUC of 0.85 (95% CI 0.78-0.91) and a pseudo-R2 value of 0.40. Of the CT scoring systems, the Helsinki CT score displayed the highest performance (AUC 0.84, 95% CI 0.78-0.90; pseudo-R2 0.39) followed by the Rotterdam CT score (AUC 0.80, 95% CI 0.73-0.86; pseudo-R2 0.34). CONCLUSIONS: Prognostic tools originally developed for the adult TBI population seemed to perform well in pediatric TBI. Of the tested CT scoring systems, the Helsinki CT score yielded the highest predictive value.

Screening for germline KCNQ1 and KCNE2 mutations in a set of somatotropinoma patients.

OBJECTIVE: Recently, mutations in KCNQ1, a potassium channel gene usually linked to long QT syndrome, were reported to cause maternally inherited gingival fibromatosis and growth hormone deficiency (GHD). Expression of the mutated KCNQ1 with the auxiliary potassium channel subunit KCNE2 was shown to reduce pituitary hormone secretion in functional experiments. Here, we investigated if germline mutations in KCNQ1 and KCNE2 were present in patients with somatotropinomas, which represent a model of growth hormone excess. DESIGN AND METHODS: KCNQ1 and KCNE2 were screened for germline mutations in 53 patients with acromegaly by Sanger sequencing. Effects of the variants were predicted by in silico tools. RESULTS: Only deep intronic and synonymous polymorphisms were detected in KCNQ1. These findings were likely insignificant based on in silico predictions and the variants' frequencies in the general population. In KCNE2, a heterozygous c.22A>G, p.(Thr8Ala) mutation with unknown significance was found in three patients. It was present in the database controls with a frequency of 0.0038. CONCLUSIONS: KCNQ1 or KCNE2 mutations do not appear to account for somatotropinoma formation, although larger patient series are needed to validate the findings.

Molecular alterations in pediatric brainstem gliomas.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPGs) have a dismal prognosis. Previously, diagnosis was based on a typical clinical presentation and magnetic resonance imaging findings. After the start of the era of biopsies, DIPGs bearing H3 K27 mutations have been reclassified into a novel entity, diffuse midline glioma, based on the presence of this molecular alteration. However, it is not well established how clinically diagnosed DIPG overlap with H3 K27-mutated diffuse midline gliomas, and whether rare long-term survivors also belong to this group. METHODS: We studied tumor samples obtained at diagnosis or upon autopsy from 23 children, including two long-term survivors. Based on clinical, radiological, and histological findings, all tumors were previously diagnosed as DIPGs. All samples were analyzed for genetic alterations by next-generation sequencing (NGS) and for protein expression by immunohistochemistry (IHC). RESULTS: H3 K27 was mutated in NGS or IHC in 20 patients, excluding both long-term survivors. One of these long-term survivors harbored a mutation in IDH1, formerly considered to be an alteration absent in pediatric diffuse brainstem gliomas. Other altered genes in NGS included TP53 (10 patients), MET and PDGFRA (3 patients each), VEGFR and SMARCA4 (2 patients each), and PPARγ, PTEN and EGFR in 1 patient, respectively. IHC revealed cMYC expression in 15 of 24 (63%) of all samples, exclusively in the biopsies. CONCLUSIONS: Eighty-seven percent of the tumors formerly diagnosed as DIPGs could be reclassified as H3 K27-mutated diffuse midline gliomas. Both long-term survivors lacked this alteration. Contrary to former conceptions, IDH1 mutations may occur also in pediatric brainstem gliomas.

Cerebellar mutism syndrome in children with brain tumours of the posterior fossa.

BACKGROUND: Central nervous system tumours constitute 25% of all childhood cancers; more than half are located in the posterior fossa and surgery is usually part of therapy. One of the most disabling late effects of posterior fossa tumour surgery is the cerebellar mutism syndrome (CMS) which has been reported in up to 39% of the patients but the exact incidence is uncertain since milder cases may be unrecognized. Recovery is usually incomplete. Reported risk factors are tumour type, midline location and brainstem involvement, but the exact aetiology, surgical and other risk factors, the clinical course and strategies for prevention and treatment are yet to be determined. METHODS: This observational, prospective, multicentre study will include 500 children with posterior fossa tumours. It opened late 2014 with participation from 20 Nordic and Baltic centres. From 2016, five British centres and four Dutch centres will join with a total annual accrual of 130 patients. Three other major European centres are invited to join from 2016/17. Follow-up will run for 12 months after inclusion of the last patient. All patients are treated according to local practice. Clinical data are collected through standardized online registration at pre-determined time points pre- and postoperatively. Neurological status and speech functions are examined pre-operatively and postoperatively at 1-4 weeks, 2 and 12 months. Pre- and postoperative speech samples are recorded and analysed. Imaging will be reviewed centrally. Pathology is classified according to the 2007 WHO system. Germline DNA will be collected from all patients for associations between CMS characteristics and host genome variants including pathway profiles. DISCUSSION: Through prospective and detailed collection of information on 1) differences in incidence and clinical course of CMS for different patient and tumour characteristics, 2) standardized surgical data and their association with CMS, 3) diversities and results of other therapeutic interventions, and 4) the role of host genome variants, we aim to achieve a better understanding of risk factors for and the clinical course of CMS - with the ultimate goal of defining strategies for prevention and treatment of this severely disabling condition. TRIAL REGISTRATION: Clinicaltrials.gov : NCT02300766 , date of registration: November 21, 2014.

Impact of AIP and inhibitory G protein alpha 2 proteins on clinical features of sporadic GH-secreting pituitary adenomas.

INTRODUCTION: In sporadic acromegaly, downregulation of AIP protein of the adenomas associates with invasive tumor features and reduced responsiveness to somatostatin analogues. AIP is a regulator of Gai signaling, but it is not known how the biological function of the Gai pathway is controlled. AIM: To study GNAS and AIP mutation status, AIP and Gai-2 protein expressions, Ki-67 proliferation indices and clinical parameters in patients having primary surgery because of acromegaly at a single center between years 2000 and 2010. RESULTS: Sixty patients (F/M, 31/29), mean age 49 (median 50), mean follow-up 7.7 years (range 0.6-14.0) underwent primary surgery. Four adenoma specimens (6.8%) harbored an AIP and 21 (35.6%) an activating GNAS (Gsp+) mutation. Altogether 13/56 (23%) adenomas had low AIP protein levels, and 14/56 (25%) low Gai-2 staining. In regression modeling, AIP expression associated with Gai-2 (P = 2.33 × 10-9) and lower Ki-67 (P = 0.04). In pairwise comparison, low AIP protein predicted high GH at last follow-up (mean 7.7 years after surgery, q = 0.045). Extent of treatments given for acromegaly associated with higher preoperative GH (P = 7.94 × 10-4), KNOSP (P = 0.003) and preoperative hypopituitarism (P = 0.03) and remission at last follow-up with change in 3-month postoperative IGF1 (P = 2.07 × 10-7). CONCLUSIONS: We demonstrate, for the first time, that AIP protein expression associates with Gai-2 protein intensities in sporadic somatotropinomas, suggesting a joint regulation on somatostatin signaling. Low AIP level associates with higher proliferative activity and predicts high GH concentrations after long-term follow-up. The AIP mutation rate of 6.8% is fairly high, reflecting the genetic composition of the Finnish population.

Health-related quality of life in patients treated for nonfunctioning pituitary adenomas during the years 2000-2010.

OBJECTIVE: The published data on health-related quality of life (HRQoL) after treatment of nonfunctioning pituitary adenomas (NFPAs) are conflicting. We evaluated HRQoL in a recent series of patients who had surgery for an NFPA. DESIGN: Cross-sectional study including a large control population. PATIENTS AND MEASUREMENTS: A HRQoL questionnaire (15D) was sent to all patients (n = 161) having undergone transsphenoidal surgery for NFPA in the years 2000-2010 at the Helsinki University Hospital. The 15D score and dimension scores of the study population (n = 137) were compared with those of a large (n = 4967) gender- and age-standardized control population. Possible independent predictors of HRQoL in the patients were estimated with multivariate regression analysis. RESULTS: Postoperatively, 57% of the patients had normal visual function. After a mean follow-up of 7·4 ± 3·2 years (mean ± SD), 62% suffered from hypopituitarism. Overall, HRQoL was near-normal in patients compared to controls (15D scores 0·885 ± 0·114 vs 0·903 ± 0·093, respectively, P = 0·07). On single dimensions, patients had impaired vision and sexual activity (both P < 0·0005), more depression and distress (both P < 0·005) and less discomfort and symptoms (P < 0·05). Age, body mass index, diabetes, depression and reoperation were independent predictors of impaired HRQoL (all P < 0·05). Thyroxine substitution was associated with impaired and hydrocortisone and testosterone substitution (males only) with better HRQoL (all P < 0·05). CONCLUSIONS: This recent series of NFPA patients demonstrates that overall HRQoL is near-normal after medium term follow-up; the most impaired dimensions were in vision and sexual activity. Comorbidities are strong predictors of impaired HRQoL.

Whole-Genome Sequencing of Growth Hormone (GH)-Secreting Pituitary Adenomas.

CONTEXT: The somatic landscape of pituitary adenomas is largely unknown. Identification of somatic alterations aims at better understanding of tumor pathology. OBJECTIVE: The objective of the study was a genome-wide characterization of somatic single-nucleotide variants, structural variants, and copy-number aberrations in somatotropinomas. DESIGN AND SETTING: Whole-genome sequencing and single-nucleotide polymorphism array analyses were performed on 12 fresh-frozen somatotropinomas and their corresponding blood samples. All the coding somatic variants were confirmed by Sanger sequencing. PATIENTS: Studied tumors were somatotropinomas. Apart from one AIP mutation-positive patient, all cases were mutation negative for the established germline mutations associated with pituitary adenomas. INTERVENTION(S): There were no interventions. MAIN OUTCOME MEASURES: Somatic variants were identified with an established computational pipeline and filtered against germline data. Somatic copy number alteration analyses were performed using segmentation-based approaches. RESULTS: A genome-wide analysis revealed on average 129 somatic single-nucleotide variants per tumor. Further analysis of coding regions showed on average 2.3 single-nucleotide variants per tumor. The only recurrent somatic events were the oncogenic GNAS mutation (p.Arg201Cys) and shared chromosome losses (chromosomes 1, 6, 13, 14, 15, 16, 18, 22). Analysis of somatic structural variants revealed one tumor with a complex chromosomal rearrangement. CONCLUSIONS: Somatotropinomas showed a low number of somatic genetic alterations. Whereas no novel recurrently mutated genes could be identified, the somatic landscape has potential to affect the Ca(2+) and ATP pathways known to be involved in the pituitary tumorigenesis. Further studies, eg, methylome and transcriptome analyses, are needed to investigate possible interplay between the recurrent chromosome losses and epigenetic factors.

Transition From Microscopic to Endoscopic Transsphenoidal Surgery for Nonfunctional Pituitary Adenomas.

OBJECTIVE: At our institution, a total of 320 patients were operated on between 2000 and 2010 for a newly diagnosed pituitary adenoma. In an attempt to improve quality of tumor resection, the transsphenoidal microscopic technique was replaced by the endoscopic technique in June 2008. This retrospective single center study compares the outcomes after microscopic (n = 144) and endoscopic (n = 41) tumor surgery of all patients operated on for a nonfunctional pituitary adenoma. METHODS: Tumor size and location, Knosp grade, prevalence of anterior hypopituitarism, diabetes insipidus, visual acuity/fields, complication rates, and operation time were compared between the groups. RESULTS: At the 3-month follow-up, hypopituitarism had improved in 7% of patients in the microscopic group and in 9% in the endoscopic group, and had further impaired in 13% and 9%, respectively. At the 3-month follow-up magnetic resonance imaging, a total tumor removal was achieved in 45% versus 56% of patients, respectively (P = not significant [NS]). Visual fields had normalized or improved in 90% versus 88% of patients, respectively (P = NS). Postoperative cerebrospinal fluid leak occurred in 3.5% versus 2.4% (P = NS), and diabetes insipidus (transient or permanent) in 7.6% versus 4.9% (P = NS) of cases, respectively. Larger tumor size (P < 0.0005) and endoscopic technique (P = 0.03) were independent predictors of increased mean operative time. CONCLUSIONS: Initial results with the endoscopic technique were statistically similar to those achieved with the microscopic technique. However, there was a trend toward improved outcomes and fewer complications in the endoscopic group.

Normal long-term health-related quality of life can be achieved in patients with functional pituitary adenomas having surgery as primary treatment.

BACKGROUND: Previous studies report impaired health-related quality of life (HRQoL) in patients with functional pituitary adenomas (FPA). We assessed HRQoL in FPA patients having undergone surgery at our University Central Hospital between 2000 and 2010, with combined adjuvant treatment given to achieve strict hormonal control. DESIGN: A cross-sectional study including a large control population. PATIENTS AND METHODS: HRQoL was assessed by the 15D in 100 FPA patients (acromegaly n = 47, Cushing's disease n = 21, prolactinoma n = 26, TSH-adenoma n = 2, gonadotropinoma n = 4), operated on a mean 7·4 (range 2·1-13·0) years earlier. An age- and gender-standardized sample of the general population (n = 4924) served as controls. HRQoL determinants were assessed by independent samples t-test and multiple regression analysis. RESULTS: Hormonal remission rate was 90·9% and 43·9% of the patients received replacement therapy. The mean 15D scores were similar in patients and controls (0·917 vs 0·922, P = 0·568). On single dimensions, patients were worse off regarding speech and sexual activity (both P < 0·05) and better off regarding discomfort and symptoms (P < 0·05). Age (P = 0·001), co-morbidities (P = 0·009), Cushing's disease (P = 0·034), and thyroxine dose (P = 0·002) predicted impaired HRQoL, but not hypopituitarism, hydrocortisone replacement, radiotherapy, or time after surgery. CONCLUSIONS: It is possible to achieve near-normal HRQoL in surgically treated FPA patients given adjuvant treatment to achieve strict hormonal remission. However, in addition to age and co-morbidities, Cushing's disease and need for thyroxine replacement therapy predict impaired HRQoL.

Prospective flutemetamol positron emission tomography and histopathology in normal pressure hydrocephalus.

UNLABELLED: BACKGOUND/OBJECTIVE: To determine the level of association between uptake of the amyloid positron emission tomography (PET) imaging agent [(18)F]flutemetamol and the level of amyloid-ß measured by immunohistochemical and histochemical staining in a frontal cortical region biopsy site. METHODS: Seventeen patients with probable normal pressure hydrocephalus (NPH) underwent prospective [(18)F]flutemetamol PET and subsequent frontal cortical brain biopsy during ventriculoperitoneal shunting. Tissue amyloid-ß was evaluated using the monoclonal antibody 4G8, thioflavin S and Bielschowsky silver stain. RESULTS: Four of the 17 patients (23.5%) had amyloid-ß pathology based on the overall pathology read and also showed increased [(18)F]flutemetamol uptake. [(18)F]Flutemetamol standardized uptake values from the biopsy site were significantly associated with biopsy specimen amyloid-ß levels (Pearson's r = 0.67; p = 0.006). There was also good correlation between the biopsy specimen amyloid-ß level and uptake of [(18)F]flutemetamol in the region contralateral to the biopsy site (r = 0.67; p = 0.006), as well as with composite cortical [(18)F]flutemetamol uptake (r = 0.65; p = 0.008). The blinded visual read showed a high level of agreement between all readers (κ = 0.88). Two of 3 readers were in full agreement on all images; 1 reader disagreed on 1 of the 17 NPH cases. Blinded visual assessments of PET images by 1 reader were associated with 100% sensitivity to the overall pathology read, and assessments by the 2 others were associated with 75% sensitivity (overall sensitivity by majority read was 75%); specificity of all readers was 100%. CONCLUSIONS: [(18)F]Flutemetamol detects brain amyloid-ß in vivo and shows promise as a valuable tool to study and possibly facilitate diagnosis of Alzheimer's disease both in patients with suspected NPH and among the wider population.