Pilot Validation of a 3-Dimensional Printed Pituitary Adenoma, Vascular Injury, and Cerebrospinal Fluid Leak Surgical Simulator.

BACKGROUND AND OBJECTIVES: Endoscopic skull base surgery is a subspecialty field which would benefit significantly from high-fidelity surgical simulators. Giving trainees the opportunity to flatten their learning curve by practicing a variety of procedures on surgical simulators will inevitably improve patient outcomes. METHODS: Four neurosurgeons, 8 otolarynologists, and 6 expert course faculty agreed to participate. All participants were asked to perform a transsphenoidal exposure and resection of a pituitary adenoma, repair a cerebrospinal fluid (CSF) leak, control a carotid injury, and repair a skull base defect. The content, face, and construct validity of the 3-dimensional printed model was examined. RESULTS: The heart rate of the participants significantly increased from baseline when starting the carotid injury simulation (mean 90 vs 121, P = .029) and significantly decreased once the injury was controlled (mean 121 vs 110, P = .033, respectively). The participants reported a significant improvement in anxiety in facing a major vascular injury, as well as an increase in their confidence in management of major vascular injury, resecting a pituitary adenoma and repair of a CSF leak using a 5-point Likert scale (mean 4.42 vs 3.58 P = .05, 2 vs 3.25 P < .001, 2.36 vs 4.27 P < .001 and 2.45 vs 4.0 P = .001, respectively). The mean Objective Structured Assessment of Technical Skills score for experienced stations was 4.4, significantly higher than the Objective Structured Assessment of Technical Skills score for inexperienced stations (mean 3.65, P = .016). CONCLUSION: We have demonstrated for the first time a validated 3-dimensional printed surgical simulator for endoscopic pituitary surgery that allows surgeons to practice a transsphenoidal approach, surgical resection of a pituitary adenoma, repair of a CSF leak in the diaphragma sellae, control of a carotid injury, and repair of skull base defect.

Increased prevalence of germline pathogenic CHEK2 variants in individuals with pituitary adenomas.

CONTEXT: CHEK2 is a cell cycle checkpoint regulator gene with a long-established role as a clinically relevant, moderate risk breast cancer predisposition gene, with greater risk ascribed to truncating variants than missense variants. METHODS: We assessed 165 individuals with pituitary adenomas for CHEK2 variants. The study consisted of a primary cohort of 29 individuals who underwent germline and tumour whole exome sequencing, and a second, independent cohort of 136 individuals who had a targeted next-generation sequencing panel performed on both germline and tumour DNA (n=52) or germline DNA alone (n=84). RESULTS: We identified rare, coding, non-synonymous germline CHEK2 variants amongst 3/29 (10.3%) patients in our primary cohort and 5/165 (3.0%) patients overall, with affected patients having a range of hormone secretion types (prolactinoma, thyrotrophinoma, somatotrophinoma and non-functioning pituitary adenoma). No somatic variants were identified. Two variants were definitive null variants (c.1100delC, c.444+1G>A), classified as pathogenic. Two variants were missense variants (p.Asn186His, p.Thr476Met), classified as likely pathogenic. Even when considering the null variants only, the rate of CHEK2 variants was higher in our cohort compared to national control data (1.8% vs. 0.5%, P=0.049). CONCLUSIONS: This is the first study to suggest a role for the breast cancer predisposition gene, CHEK2, in pituitary tumorigenesis, with pathogenic/likely pathogenic variants found in 3% of patients with pituitary adenomas. As pituitary adenomas are relatively common and typically lack classical autosomal dominant family histories, risk alleles - such as these variants found in CHEK2 - might be a significant contributor to pituitary adenoma risk in the general population.

The Learning Curve for Endoscopic Endonasal Transsphenoidal Pituitary Surgery: Evaluating Endocrine Outcomes.

OBJECTIVE: In South Australia endoscopic endonasal approach (EEA) pituitary surgery has been practiced since 2006, largely by two neurosurgeons with a small fellowship-trained otolaryngology team. The aim of this cohort study was to determine if a "learning curve" can be established over this time period, as represented by structural and endocrine patient outcomes. METHOD: Retrospective cohort study of patients undergoing EEA surgery between 2006 and 2021 in Adelaide, South Australia at three tertiary teaching hospitals.. Cases were divided by each surgeon and split into groups of sequential 40 cases. Endocrine assessment pre- and post-operatively involved static pituitary and end-organ hormones, with dynamic tests as required, assessed by an pituitary endocrinologist. Each hormonal axis (gonadal, cortisol, thyroid, prolactin and growth hormone) was documented preoperatively and at an early and long term follow up at 1-2 and 12 months, respectively. RESULTS: The study included a cohort of 443 pituitary adenomas managed with endoscopic endonasal transsphenoidal surgery in a consecutive fashion between two neurosurgeons over 16-years. Gross tumour resection but not visual visual outcomes improved with surgical experience but this outcome may be neurosurgeon dependent. Endocrine outcomes were not consistently improved with experience, but lower rates of hypopituitarism were seen with experience with one neurosurgeon. Average follow up was approximately 5 years, and a minimum follow up of 12 months for all patients. CONCLUSIONS: We present long term endocrine follow up for patients with functional and non-functional adenomas. Improved rates of gross tumour resection were evident with with surgical experience. However, there was no apparent change in post-operative endocrine outcomes.

PAM variants in patients with thyrotrophinomas, cyclical Cushing's disease and prolactinomas.

Introduction: Germline loss-of-function variants in PAM, encoding peptidylglycine α-amidating monooxygenase (PAM), were recently discovered to be enriched in conditions of pathological pituitary hypersecretion, specifically: somatotrophinoma, corticotrophinoma, and prolactinoma. PAM is the sole enzyme responsible for C-terminal amidation of peptides, and plays a role in the biosynthesis and regulation of multiple hormones, including proopiomelanocortin (POMC). Methods: We performed exome sequencing of germline and tumour DNA from 29 individuals with functioning pituitary adenomas (12 prolactinomas, 10 thyrotrophinomas, 7 cyclical Cushing's disease). An unfiltered analysis was undertaken of all PAM variants with population prevalence <5%. Results: We identified five coding, non-synonymous PAM variants of interest amongst seven individuals (six germline, one somatic). The five variants comprised four missense variants and one truncating variant, all heterozygous. Each variant had some evidence of pathogenicity based on population prevalence, conservation scores, in silico predictions and/or prior functional studies. The yield of predicted deleterious PAM variants was thus 7/29 (24%). The variants predominated in individuals with thyrotrophinomas (4/10, 40%) and cyclical Cushing's disease (2/7, 29%), compared to prolactinomas (1/12, 8%). Conclusion: This is the second study to demonstrate a high yield of suspected loss-of-function, predominantly germline, PAM variants in individuals with pathological pituitary hypersecretion. We have extended the association with corticotrophinoma to include the specific clinical entity of cyclical Cushing's disease and demonstrated a novel association between PAM variants and thyrotrophinoma. PAM variants might act as risk alleles for pituitary adenoma formation, with a possible genotype-phenotype relationship between truncating variants and altered temporal secretion of cortisol.

Recommendations on screening mammography in patients with ventriculoperitoneal shunts and deep brain stimulation.

Insertion of ventriculoperitoneal (VP) shunt and deep brain stimulation (DBS) are common neurosurgical procedures. Concerns have been raised regarding the safety of mammography in this patient cohort due to the risk of damaging the VP shunt tubing or DBS implantable pulse generator, and the degradation in mammography image quality secondary to the implanted devices. Based on a review of the current literature, the authors propose that mammography is safe in patients with VP shunts and DBS, and should be performed routinely as a part of population screening.

Secondary Raised Intracranial Pressure After Cranial Vault Remodeling for Isolated Sagittal Craniosynostosis.

ABSTRACT: The management of sagittal craniosynostosis has evolved over the decades as teams seek to refine their surgical approaches to idealize head shape with the least possible morbidity. Here, the authors identify the incidence of raised intracranial pressure (ICP) and its risk factors, requiring secondary surgical intervention after cranial vault remodeling (CVR) procedure at a single tertiary referral craniofacial unit. A retrospective case-control study was performed on the patients with isolated non-syndromic sagittal craniosynostosis. All patients who underwent CVR in our unit and had a minimum of 1.5 years follow-up were included. One hundred and eighty-four patients (134 male and 50 female) who underwent primary CVR surgery for isolated sagittal craniosynostosis were included. Thirteen patients (7.07%) had clinical evidence of late raised ICP resulting in repeat CVR procedures. Higher incidence of raised ICP in patients who had primary surgery before 6 months than after or at 6 months of age (P = 0.001). There were 23.5%, 5.6%, 3.2%, and 1.9% of secondary raised ICP patients who underwent the primary surgery between 1999-2004, 2005-2010, 2011-2015 and 2016-2018, respectively (P = 0.024). The risk of secondary raised ICP was higher in patients with isolated sagittal craniosynostosis whose primary surgery occurred before the age of 6 months (two times more likely). More extensive CVR can be performed safely in sagittal synostosis with promising outcomes. The late presentation with raised ICP reinforces the importance of long-term multidisciplinary protocol-based follow-up.

Outcomes of surgical resection of sphenoid-orbital meningiomas with Sonopet ultrasonic aspirator.

Purpose: Surgical resection is the mainstay of treatment for spheno-orbital meningiomas. The Sonopet® is an ultrasonic aspirator device that provides several advantages over the traditional standard suction techniques and bone drill, including decreased collateral soft tissue damage, more precise bone removal and a clearer operative field. The purpose of the study was to examine the treatment outcomes of Sonopet®-assisted resection of spheno-orbital meningiomas.Methods: A retrospective chart review was conducted in seven patients with spheno-orbital meningioma in a single institution who underwent surgical resection with the Sonopet®. Pre-operative and post-operative data included the assessment of visual acuity, relative afferent pupillary defect (RAPD), Ishihara score, proptosis, fundus examination, computerised visual fields and the presence or absence of diplopia, headache, and other neuro-ophthalmic complications.Results: Nine Sonopet®-assisted procedures were performed on seven patients. Post-operatively, 89% of cases had stabilization or improvement of visual acuity and colour vision, whilst 29% had improved visual fields with the remainder being stable. Proptosis improved in all patients. Five of nine cases (44%) had new post-operative cranial nerve palsies, of which 75% were transient. One patient had tumour recurrence after 14 months, requiring further tumour resection and radiotherapy.Conclusion: Sonopet®-assisted resection of spheno-orbital meningiomas has comparable outcomes of visual improvement and complication rates to traditional resection techniques. Longer periods of post-operative observation and follow-up are recommended to observe long-term benefits.

The Genomic Landscape of Sporadic Prolactinomas.

Somatic GNAS and USP8 mutations have been implicated in sporadic somatotrophinomas and corticotrophinomas, respectively. However, no genes are known to be recurrently mutated in sporadic prolactinomas. The prevalence of copy number variants (CNV), which is emerging as a mechanism of tumorigenesis in sporadic pituitary adenomas in general, is also unclear in prolactinomas. To characterize the genetic events underpinning sporadic prolactinomas, we performed whole exome sequencing of paired tumor and germline DNA from 12 prolactinoma patients. We observed recurrent large-scale CNV, most commonly in the form of copy number gains. We also identified sequence variants of interest in 15 genes. This included the DRD2, PRL, TMEM67, and MLH3 genes with plausible links to prolactinoma formation. Of the 15 genes of interest, CNV was seen at the gene locus in the corresponding tumor in 10 cases, and pituitary expression of eight genes was in the top 10% of tissues. However, none of our shortlisted somatic variants appeared to be classical driver mutations as no variant was found in more than one tumor. Future directions of research include mechanistic studies to investigate how CNV may contribute to prolactinoma formation, larger studies of relevant prolactinoma subsets according to clinical characteristics, and additional genetic investigations for aberrations not captured by whole exome sequencing.

Successful repair of intraoperative cerebrospinal fluid leaks improves outcomes in endoscopic skull base surgery.

BACKGROUND: The impact of failed cerebrospinal fluid leak (CSF) leak repair in endoscopic skull base surgery has not been adequately studied. METHODS: In this investigation we reviewed patients who had undergone endoscopic skull base surgery between 2002 and 2014 at 7 international centers. Demographic variables, comorbidities, tumor characteristics, and repair techniques were evaluated to determine association with successful repair of CSF leak. Postoperative complications and length of stay were compared among groups. RESULTS: Data were collected on 2097 patients who were divided into 3 groups: (1) those with no intraoperative leak (n = 1533); (2) those with successful repair of their intraoperative leak (n = 452); and (3) those with failed repair (n = 112). Compared with successful repair, failed repair was associated with an increased risk of intracranial infection (odds ratio [OR], 5.6; 95% confidence interval [CI], 5.3-13.15), pneumocephalus (OR, 16; 95% CI, 5.8-44.4), 30-day readmission (OR, 8.4; 95% CI, 5.3-13.5), reoperation (OR, 115.4; 95% CI, 56.3-236.8), and prolonged hospital stay (14.9 vs 7.0 days, p < 0.01). Outcomes in patients who had successful repairs of intraoperative leaks were similar to those who never had leakage. Intraoperative use of pedicled nasoseptal flaps was associated with successful repair (OR, 0.60; 95% CI, 0.34-0.92). CONCLUSION: Intraoperative CSF leaks are a frequent and expected occurrence during endoscopic skull base surgery. Failed CSF leak repair has a significant impact on patient outcomes, with increased rates of postoperative pneumocephalus, intracranial infections, reoperation, deep vein thrombosis, readmission, and prolonged hospital stay. Recognition and repair of intraoperative CSF leaks reduces postoperative complications. Use of pedicled nasoseptal flaps improves outcomes in reconstructing defects at higher risk for postoperative leak.

Apert syndrome: Surgical outcomes and perspectives.

PURPOSE: Apert syndrome is a rare congenital malformation with severe craniofacial anomalies. The aim of this study was to review the outcomes of craniofacial and neurosurgical interventions in Apert syndrome patients treated at a single institution. MATERIALS AND METHODS: A retrospective review of all patient records with a diagnosis of Apert syndrome assessed and managed in the Australian Craniofacial Unit (ACFU) from 1985 to 2013 was conducted. RESULTS: A total of 94 patients were identified, and 130 transcranial procedures were performed. Of the patients, 83 underwent a fronto-orbital advancement (FOA) as their primary procedure, and 18 patients also underwent a posterior vault procedure. Twenty patients underwent a fronto-facial monobloc advancement. Overall, 70% of patients underwent at least 2 transcranial procedures. Shunts were inserted in 2 patients preoperatively and in 5 patients postoperatively for cerebrospinal fluid (CSF) leaks or acute hydrocephalus. Re-do FOAs were performed in 8 patients. Patients who underwent an FOA at the age of more than 18 months had no recurrence of raised intracranial pressure (ICP). Of 18 patients who also underwent a posterior vault procedure, 1 patient had recurrence of raised ICP. Midfacial surgery was performed early if there was evidence of obstructive sleep apnoea (OSA), but delayed midfacial surgery was preferred. Complications were reported in 18% of procedures. The most common complications were CSF leaks and acute hydrocephalus. CONCLUSION: Shunting is rarely required in Apert syndrome patients, confirming a predominantly nonprogressive ventriculomegaly. FOA appears to be a more stable procedure when performed at an age of more than 18 months. Undergoing a posterior vault procedure may reduce the risk of recurrent raised ICP and lead to fewer transcranial procedures needed in childhood. Midfacial surgery should be delayed until adolescence where there is no evidence of OSA, psychological disturbance, or complications of exorbitism. Complications are rare when these patients are treated by an experienced craniofacial team.

Central nervous system and cervical spine abnormalities in Apert syndrome.

PURPOSE: Apert syndrome characterized by acrocephalosyndactyly is a rare autosomal dominant congenital malformation with a prevalence of 1/65,000 births. With an extensive range of phenotypic and developmental manifestations, its management requires a multidisciplinary approach. A variety of craniofacial, central nervous system (CNS), and cervical spine abnormalities have been reported in these patients. This study aimed to determine the incidence of these CNS abnormalities in our case series. METHODS: Retrospective review of Australian Craniofacial Unit (ACFU) database for Apert patients was performed. Data collected that included demographics, place of origin, age at presentation, imaging performed, and images were reviewed and recorded. Where available, developmental data was also recorded. RESULTS: Ninety-four patients seen and managed at the ACFU had their CNS and cervical spine abnormalities documented. The main CNS abnormalities were prominent convolutional markings (67 %), ventriculomegaly (48 %), crowded foramen magnum (36 %), deficient septum pellucidum (13 %), and corpus callosum agenesis in 11 %. Major C-spine findings were present in 50.8 % of patients and included fusion of posterior elements of C5/C6 (50 %) and C3/4 (27 %). Multilevel fusion was seen in 20 %. Other abnormalities were C1 spina bifida occulta (7 %) and atlanto-axial subluxation (7 %). CONCLUSION: Multiple CNS and cervical spine (c-spine) abnormalities are common in Apert syndrome. The significance of these abnormalities remains largely unknown. Further research is needed to better understand the impact of these findings on growth, development, and treatment outcomes.

Trigeminal neuralgia associated with Chiari 1 malformation: symptom resolution following craniocervical decompression and duroplasty: Case report and review of the literature.

BACKGROUND: Trigeminal neuralgia (TN) may rarely be the presenting or only symptom of Chiari 1 malformation (CM). Isolated case reports have described resolution of TN following craniocervical decompression where TN is present in association with CM. CASE REPORT: This report discusses an unusual case of pure TN associated with CM that was successfully treated with craniocervical decompression and duroplasty and reviews the limited literature on the subject. CONCLUSION: TN may be the sole presenting symptom of CM and can be successfully managed with craniocervical decompression. Clinicians should be aware of the association of TN with CM and consider surgical management.

Update on endoscopic endonasal resection of skull base meningiomas.

BACKGROUND: The objective of this work was to report success rates as well as potential obstacles in transnasal endoscopic resection of anterior skull base meningiomas. METHODS: The study design was a case series with chart review at tertiary referral centers in South Australia and New Zealand. The patients were 37 consecutive patients who underwent endoscopic resection of skull-base meningiomas between 2004 and 2013. Review of patient charts and operative details were performed. Outcomes including complications are reported. RESULTS: Eighty-four percent of patients were women. There were 28 primary and 9 revision cases. Tumor locations were as follows: 14 olfactory groove/subfrontal; 12 planum/jugum sphenoidale; 7 tuberculum sellae; 3 clinoidal; and 1 clival. Vision change was the most common presenting symptom. Mean tumor volume was 33.68 cm(3) , mean diameter was 2.78 cm. Average operating times decreased with an initial learning curve and then plateaued. Primary tumors larger than 60 cm(3) took an average of 10 hours to resect. Gross total removal was achieved in 29 patients. There were no perioperative deaths. Two deaths occurred within 1 year of surgery. Postoperative cerebrospinal fluid (CSF) leaks occurred in 13 patients. Seventy-five percent of patients presenting with visual loss reported visual improvement. Of the 29 patients considered to have had complete resection at surgery, one was found to have residual disease on a postoperative magnetic resonance imaging (MRI) and another one later developed radiological evidence of recurrence. CONCLUSION: Using a 2-team approach, meningiomas of the skull base were successfully removed via an intranasal endoscopic technique. Although complete resection is typically possible even with large tumors, the lengthy resection required time for tumors larger than 60 cm(3) (diameter ≥4 cm) may obviate some of the advantages of this approach. The rate of postoperative CSF leak decreases when a synthetic dural substitute is added but does not approach zero.

Endoscopic endonasal resection of anterior skull base meningiomas.

OBJECTIVE: Anterior cranial fossa (ACF) meningiomas are difficult to surgically manage. Endoscopic transnasal approaches have increasingly been used as a minimally invasive route and thus offer significant advantages. However, a paucity of literature describing the intraoperative challenges and postoperative outcomes of this technique still exists. STUDY DESIGN: Case series with chart review. SETTING: The Royal Adelaide Hospital, Flinders Medical Centre, Wellington Hospital. SUBJECTS AND METHODS: Fifteen consecutive patients who underwent endoscopic resection of ACF meningiomas between 2004 and 2010 by the South Australian and Wellington Skull Base Units. Demographic and clinical information was compiled by reviewing patient charts and operation notes. Safety and efficacy of the procedure, role of a team approach, and areas for further improvement were analyzed. RESULTS: Of the patients, 87% were women. Tumor locations: 8 olfactory groove, 2 tuberculum sellae, 1 clinoidal, 1 jugum sphenoidale, 1 planum sphenoidale, 1 subfrontal, and 1 midline ACF floor. Commonest presenting symptom was visual change. Mean volume of tumor was 25.69 cm(3), with a size area of 7.28 cm(2). Five were revision cases. None had previous endonasal surgery. Average operating times decreased over time. Gross total removal was achieved in 14, with no deaths. Four patients had postoperative cerebrospinal fluid (CSF) leak. Rate of CSF leak decreased over time. Sixty percent of patients reported visual improvement. Two patients had radiological evidence of recurrence. CONCLUSION: ACF meningiomas can be safely removed endonasally, offering significant advantages over the traditional transcranial approach for suitable tumors. Early audit of this approach shows results achieved by this unit are comparable with the published literature.

Colloid cyst of velum interpositum: a rare finding.

The authors present the case of a child with a colloid cyst of the velum interpositum. To the best of the authors' knowledge, this is the first reported case in the pediatric literature and only the second reported case to date. The patient was of an 11-year-old boy in whom this lesion was found after a minor head injury. He had a 6-month history of memory deficits. A lesion consistent with a colloid cyst was seen in the region of the velum interpositum, in the roof of the third ventricle. This lesion was excised successfully via a transcallosal interfornical approach. There were no new postoperative deficits and the child made a full recovery of time.

Modified transoral approach for resection of skull base chordomas in children.

PURPOSE: Chordomas are rare slow growing, locally destructive tumours originating from remnants of the primitive notocord and are found most commonly in the clivus and saccrococcygeal region. These tumours usually present in early adult life but on occasion can present in childhood. The combination of the skull base location and paediatric patient size makes access to these tumours particularly challenging. METHODS AND RESULTS: We report a multidisciplinary technique used in two cases in children where a modified extended palatal split was undertaken to allow greater access for tumour excision. CONCLUSION: This approach allows for good access to the skull base region to allow for maximal tumour resection. This technique also appears to have minimal impact on palatal function and no adverse effects on the upper airway management.