Development and evaluation of image-guided neuroendoscopy, with investigation of post-imaging brain distortion and accuracy of frameless stereotaxy

Neuroendoscopy enables a surgeon to operate deep within the brain whilst limiting morbidity through a minimally invasive approach. Technical advances in illumination, instrumentation and camera design, along with evidence for improved clinical outcome, have increased the indications for this technique and have ensured widespread popularity. However, broader application of neuroendoscopy is restricted by the necessity for direct vision of targets and by spatial disorientation. The aim of this investigation was to overcome these limitations by combining neuronavigation with neuroendoscopy to develop Image-Guided Neuroendoscopy (IGN). The strategy adopted for this was firstly to select, assess and validate a neuronavigation system, secondly to develop methods of endoscope tracking and frameless stereotactic implantation. Thirdly, to assess the impact of post-imaging brain distortion upon neuronavigation, fourthly to correct distortion of the endoscope image and finally to assess the use of graphics overlay in IGN. Laboratory phantom accuracy assessments revealed a mean point localisation error for the navigation system pointers of0.8mm (SD 0.4mm) with CT imaging, for the tracked endoscope of 1.5mm (SD 0.8mm) and for frameless stereotaxy of 1.3mm (SD 0.6mm). An in vivo study revealed a mean Euclidean error of 4.8mm (SD 2.0mm) for frame less stereotactic biopsy. The navigation system was evaluated through a clinical series of 100 cases, the frameless stereotactic technique was employed in 21 brain biopsy procedures and IGN evaluated in 5 procedures. The magnitude of post-imaging brain distortion was determined and correlations discovered with pre-operative image characteristics. The conclusions of this thesis are that IGN can be accomplished with acceptable accuracy, including frameless stereotactic implantation, and that the impact of postimaging brain distortion will not negate the value of IGN in most cases. Thus, the method developed for IGN has overcome both major constraints of neuroendoscopy, enabling endoscopic surgery to pass through and beyond the ventricular wall, to be undertaken safely in cases with distorted anatomy and opening the potential for wider application of these minimally invasive techniques

Reliable computational quantification of liver fibrosis is compromised by inherent staining variation

Biopsy remains the gold standard measure for staging liver disease, both to inform prognosis and to assess the response to a given treatment. Semiquantitative scores such as the Ishak fibrosis score are used for evaluation. These scores are utilised in clinical trials, with the US Food and Drug Administration mandating particular scores as inclusion criteria for participants and using the change in score as evidence of treatment efficacy. There is an urgent need for improved, quantitative assessment of liver biopsies to detect small incremental changes in liver architecture over the course of a clinical trial. Artificial intelligence (AI) methods have been proposed as a way to increase the amount of information extracted from a biopsy and to potentially remove bias introduced by manual scoring. We have trained and evaluated an AI tool for measuring the amount of scarring in sections of picrosirius red-stained liver. The AI methodology was compared with both manual scoring and widely available colour space thresholding. Four sequential sections from each case were stained on two separate occasions by two independent clinical laboratories using routine protocols to study the effect of inter- and intra-laboratory staining variation on these tools. Finally, we compared these methods to second harmonic generation (SHG) imaging, a stain-free quantitative measure of collagen. Although AI methods provided a modest improvement over simpler computer-assisted measures, staining variation both within and between labs had a dramatic effect on quantitation, with manual assignment of scar proportion the most consistent. Manual assessment also correlated the most strongly with collagen measured by SHG. In conclusion, results suggest that computational measures of liver scarring from stained sections are compromised by inter- and intra-laboratory staining. Stain-free quantitative measurement using SHG avoids staining-related variation and may prove more accurate in detecting small changes in scarring that may occur in therapeutic trials

Current and Future Advances in Surgical Therapy for Pituitary Adenoma

The vital physiological role of the pituitary gland, alongside its proximal critical neurovascular structures means pituitary adenomas cause significant morbidity or mortality. Whilst enormous advancements have been made in the surgical care of pituitary adenomas, treatment failure and recurrence remain challenges. To meet these clinical challenges, there has been an enormous expansion of novel medical technologies (e.g. endoscopy, advanced imaging, artificial intelligence). These innovations have the potential to benefit each step of the patient journey, and ultimately, drive improved outcomes. Earlier and more accurate diagnosis addresses this in part. Analysis of novel patient data sets, such as automated facial analysis or natural language processing of medical records holds potential in achieving an earlier diagnosis. After diagnosis, treatment decision-making and planning will benefit from radiomics and multimodal machine learning models. Surgical safety and effectiveness will be transformed by smart simulation methods for trainees. Next-generation imaging techniques and augmented reality will enhance surgical planning and intraoperative navigation. Similarly, the future armamentarium of pituitary surgeons, including advanced optical devices, smart instruments and surgical robotics, will augment the surgeon's abilities. Intraoperative support to team members will benefit from a surgical data science approach, utilising machine learning analysis of operative videos to improve patient safety and orientate team members to a common workflow. Postoperatively, early detection of individuals at risk of complications and prediction of treatment failure through neural networks of multimodal datasets will support earlier intervention, safer hospital discharge, guide follow-up and adjuvant treatment decisions. Whilst advancements in pituitary surgery hold promise to enhance the quality of care, clinicians must be the gatekeepers of technological translation, ensuring systematic assessment of risk and benefit. In doing so, the synergy between these innovations can be leveraged to drive improved outcomes for patients of the future

Specialised Surgical Instruments for Endoscopic and Endoscope-Assisted Neurosurgery: A Systematic Review of Safety, Efficacy and Usability

While there have been great strides in endoscopic and endoscope-assisted neurosurgical approaches, particularly in the treatment of deep-sited brain and skull base tumours, the greatest technical barrier to their adoption has been the availability of suitable surgical instruments. This systematic review seeks to identify specialised instruments for these approaches and evaluate their safety, efficacy and usability. Conducted in accordance with the PRISMA guidelines, Medline, Embase, CENTRAL, SCOPUS and Web of Science were searched. Original research studies that reported the use of specialised mechanical instruments that manipulate tissue in human patients, cadavers or surgical models were included. The results identified 50 specialised instruments over 62 studies. Objective measures of safety were reported in 32 out of 62 studies, and 20 reported objective measures of efficacy. Instruments were broadly safe and effective with one instrument malfunction noted. Measures of usability were reported in 15 studies, with seven reporting on ergonomics and eight on the instruments learning curve. Instruments with reports on usability were generally considered to be ergonomic, though learning curve was often considered a disadvantage. Comparisons to standard instruments were made in eight studies and were generally favourable. While there are many specialised instruments for endoscopic and endoscope-assisted neurosurgery available, the evidence for their safety, efficacy and usability is limited with non-standardised reporting and few comparative studies to standard instruments. Future innovation should be tailored to unmet clinical needs, and evaluation guided by structured development processes

Pituitary function at presentation and following therapy in patients with non-functional pituitary macroadenomas: a single centre retrospective cohort study

Background: Non-functioning pituitary macroadenomas (NFPMs) may present with hypopituitarism. Pituitary surgery and radiotherapy pose an additional risk to pituitary function. Objectives: To assess the incidence of hypopituitarism at presentation, the impact of treatment, and the likelihood of endocrine recovery during follow-up. Methods: All patients treated surgically with and without radiotherapy for NFPMs between 1987 and 2018 who had longer than six months follow-up were identified. Demographics, presentation, investigation, treatment, and outcomes were collected. Results: In total, 383 patients were identified. The median age was 57 years, with a median follow-up of 8 years. Preoperatively, 227 patients (227/375; 61%) had evidence of at least one pituitary deficiency. Anterior panhypopituitarism was more common in men (p = 0.001) and older patients (p = 0.005). Multiple hormone deficiencies were associated with large tumours (p = 0.03). Patients treated with surgery and radiotherapy had a higher incidence of all individual pituitary hormone deficiency, anterior panhypopituitarism, and significantly lower GH, ACTH, and TSH deficiencies free survival probability than those treated with surgery alone. Recovery of central hypogonadism, hypothyroidism, and anterior panhypopituitarism was also less likely to be reported in those treated with surgery and radiotherapy. Those with preoperative hypopituitarism had a higher risk of pituitary impairment at latest review than those presented with normal pituitary function (p = 0.001). Conclusion: NFPMs are associated with a significant degree of hypopituitarism at time of diagnosis and post-therapy. The combination of surgery and radiotherapy is associated with a higher risk of pituitary dysfunction. Recovery of pituitary hormone deficit may occur after treatment. Patients should have regular ongoing endocrine evaluation post-treatment to assess changes in pituitary function and the need for long-term replacement therapy

Robotic Handle Prototypes for Endoscopic Endonasal Skull Base Surgery: Pre-clinical Randomised Controlled Trial of Performance and Ergonomics

Endoscopic endonasal skull base surgery is a promising alternative to transcranial approaches. However, standard instruments lack articulation, and thus, could benefit from robotic technologies. The aim of this study was to develop an ergonomic handle for a handheld robotic instrument intended to enhance this procedure. Two different prototypes were developed based on ergonomic guidelines within the literature. The first is a forearm-mounted handle that maps the surgeon’s wrist degrees-of-freedom to that of the robotic end-effector; the second is a joystick-and-trigger handle with a rotating body that places the joystick to the position most comfortable for the surgeon. These handles were incorporated into a custom-designed surgical virtual simulator and were assessed for their performance and ergonomics when compared with a standard neurosurgical grasper. The virtual task was performed by nine novices with all three devices as part of a randomised crossover user-study. Their performance and ergonomics were evaluated both subjectively by themselves and objectively by a validated observational checklist. Both handles outperformed the standard instrument with the rotating joystick-body handle offering the most substantial improvement in terms of balance between performance and ergonomics. Thus, it is deemed the more suitable device to drive instrumentation for endoscopic endonasal skull base surgery

High fidelity simulation of the endoscopic transsphenoidal approach: Validation of the UpSurgeOn TNS Box

Objective: Endoscopic endonasal transsphenoidal surgery is an established technique for the resection of sellar and suprasellar lesions. The approach is technically challenging and has a steep learning curve. Simulation is a growing training tool, allowing the acquisition of technical skills pre-clinically and potentially resulting in a shorter clinical learning curve. We sought validation of the UpSurgeOn Transsphenoidal (TNS) Box for the endoscopic endonasal transsphenoidal approach to the pituitary fossa./ Methods: Novice, intermediate and expert neurosurgeons were recruited from multiple centres. Participants were asked to perform a sphenoidotomy using the TNS model. Face and content validity were evaluated using a post-task questionnaire. Construct validity was assessed through post-hoc blinded scoring of operative videos using a Modified Objective Structured Assessment of Technical Skills (mOSAT) and a Task-Specific Technical Skill scoring system./ Results: Fifteen participants were recruited of which n = 10 (66.6%) were novices and n = 5 (33.3%) were intermediate and expert neurosurgeons. Three intermediate and experts (60%) agreed that the model was realistic. All intermediate and experts (n = 5) strongly agreed or agreed that the TNS model was useful for teaching the endonasal transsphenoidal approach to the pituitary fossa. The consensus-derived mOSAT score was 16/30 (IQR 14–16.75) for novices and 29/30 (IQR 27–29) for intermediate and experts (p < 0.001, Mann–Whitney U). The median Task-Specific Technical Skill score was 10/20 (IQR 8.25–13) for novices and 18/20 (IQR 17.75–19) for intermediate and experts (p < 0.001, Mann-Whitney U). Interrater reliability was 0.949 (CI 0.983–0.853) for OSATS and 0.945 (CI 0.981–0.842) for Task-Specific Technical Skills. Suggested improvements for the model included the addition of neuro-vascular anatomy and arachnoid mater to simulate bleeding vessels and CSF leak, respectively, as well as improvement in materials to reproduce the consistency closer to that of human tissue and bone./ Conclusion: The TNS Box simulation model has demonstrated face, content, and construct validity as a simulator for the endoscopic endonasal transsphenoidal approach. With the steep learning curve associated with endoscopic approaches, this simulation model has the potential as a valuable training tool in neurosurgery with further improvements including advancing simulation materials, dynamic models (e.g., with blood flow) and synergy with complementary technologies (e.g., artificial intelligence and augmented reality)

Non-functioning pituitary macroadenoma following surgery: long-term outcomes and development of an optimal follow-up strategy

OBJECTIVES: Recurrence and regrowth of non-functioning pituitary macroadenomas (NFPMs) after surgery are common but remain unpredictable. Therefore, the optimal timing and frequency of follow-up imaging remain to be determined. We sought to determine the long-term surgical outcomes of NFPMs following surgery and develop an optimal follow-up strategy. METHODS: Patients underwent surgery for NFPMs between 1987 and 2018, with a follow-up of 6 months or more, were identified. Demographics, presentation, management, histology, imaging, and surgical outcomes were retrospectively collected. RESULTS: In total, 383 patients were included; 256 were men (256/383; 67%) with median follow-up of 8 years. Following primary surgery, 229 patients (229/383; 60%) achieved complete resection. Of those, 28 (28/229; 11%) developed recurrence, including six needed secondary surgery (6/229; 3%). The rate of complete resection improved over time; in the last quartile of cases, 77 achieved complete resection (77/95; 81%). Reoperation-free survival at 5, 10 and 15 years was 99%, 94% and 94%, respectively. NFPMs were incompletely resected in 154 patients (154/383; 40%); of those, 106 (106/154; 69%) had regrowth, and 84 (84/154; 55%) required reoperation. Surgical reintervention-free survival at 5, 10 and 15 years was 74%,49% and 35%, respectively. Young age and cavernous sinus invasion were risk factors for undergoing reoperation (P < 0.001 and P < 0.0001, respectively) and radiotherapy (P = 0.003 and P < 0.001, respectively). Patients with residual tumour required reoperation earlier than those underwent complete resection (P = 0.02). Radiotherapy to control tumour regrowth was delivered to 65 patients (65/383; 17%) after median time of 1 year following surgery. Radiotherapy was administered more in patients with regrowth of residual disease (61/106; 58%) than those who had NFPMs recurrence (4/28; 14%) (P ≤ 0.001) Following postoperative radiotherapy, one patient (1/65; 2%) had evidence of regrowth, seven (7/65; 11%) had tumour regression on imaging, and no patients underwent further surgery. CONCLUSIONS: NFPMs recurrence and regrowth are common, particularly in patients with residual disease post-operatively. We propose a follow-up strategy based on stratifying patients as "low risk" if there is no residual tumour, with increasing scan intervals, or "high risk" if there is a residual tumour, with annual scans for at least five years and extended lifelong surveillance after that

Process analysis of the patient pathway for automated data collection: an exemplar using pituitary surgery

Introduction: Automation of routine clinical data shows promise in relieving health systems of the burden associated with manual data collection. Identifying consistent points of documentation in the electronic health record (EHR) provides salient targets to improve data entry quality. Using our pituitary surgery service as an exemplar, we aimed to demonstrate how process mapping can be used to identify reliable areas of documentation in the patient pathway to target structured data entry interventions. Materials and methods: This mixed methods study was conducted in the largest pituitary centre in the UK. Purposive snowball sampling identified frontline stakeholders for process mapping to produce a patient pathway. The final patient pathway was subsequently validated against a real-world dataset of 50 patients who underwent surgery for pituitary adenoma. Events were categorized by frequency and mapped to the patient pathway to determine critical data points. Results: Eighteen stakeholders encompassing all members of the multidisciplinary team (MDT) were consulted for process mapping. The commonest events recorded were neurosurgical ward round entries (N = 212, 14.7%), pituitary clinical nurse specialist (CNS) ward round entries (N = 88, 6.12%) and pituitary MDT treatment decisions (N = 88, 6.12%) representing critical data points. Operation notes and neurosurgical ward round entries were present for every patient. 43/44 (97.7%) had a pre-operative pituitary MDT entry, pre-operative clinic letter, a post-operative clinic letter, an admission clerking entry, a discharge summary, and a post-operative histopathology pituitary multidisciplinary (MDT) team entries. Conclusion: This is the first study to produce a validated patient pathway of patients undergoing pituitary surgery, serving as a comparison to optimise this patient pathway. We have identified salient targets for structured data entry interventions, including mandatory datapoints seen in every admission and have also identified areas to improve documentation adherence, both of which support movement towards automation

Reported outcomes in transsphenoidal surgery for pituitary adenomas: a systematic review

PURPOSE: Transsphenoidal surgery is an established treatment for pituitary adenomas. We examined outcomes and time points following transsphenoidal surgery for pituitary adenoma to identify reporting heterogeneity within the literature. METHODS: A systematic review of studies that reported outcomes for transsphenoidal surgery for pituitary adenoma 1990–2021 were examined. The protocol was registered a priori and adhered to the PRISMA statement. Studies in English with > 10 patients (prospective) or > 500 patients (retrospective) were included. RESULTS: 178 studies comprising 427,659 patients were included. 91 studies reported 2 or more adenoma pathologies within the same study; 53 studies reported a single pathology. The most common adenomas reported were growth hormone-secreting (n = 106), non-functioning (n = 101), and ACTH-secreting (n = 95); 27 studies did not state a pathology. Surgical complications were the most reported outcome (n = 116, 65%). Other domains included endocrine (n = 104, 58%), extent of resection (n = 81, 46%), ophthalmic (n = 66, 37%), recurrence (n = 49, 28%), quality of life (n = 25, 19%); and nasal (n = 18, 10%). Defined follow up time points were most reported for endocrine (n = 56, 31%), extent of resection (n = 39, 22%), and recurrence (n = 28, 17%). There was heterogeneity in the follow up reported for all outcomes at different time points: discharge (n = 9),  1 year (n = 69). CONCLUSION: Outcomes and follow up reported for transsphenoidal surgical resection of pituitary adenoma are heterogenous over the last 30 years. This study highlights the necessity to develop a robust, consensus-based, minimum, core outcome set. The next step is to develop a Delphi survey of essential outcomes, followed by a consensus meeting of interdisciplinary experts. Patient representatives should also be included. An agreed core outcome set will enable homogeneous reporting and meaningful research synthesis, ultimately improving patient care