Awake craniotomy with English and British sign language mapping in a patient with a left temporal glioblastoma reveals discordant speech-sign language maps.

The aim of this case study was to describe differences in English and British Sign Language (BSL) communication caused by a left temporal tumour resulting in discordant presentation of symptoms, intraoperative stimulation mapping during awake craniotomy and post-operative language abilities. We report the first case of a hearing child of deaf adults, who acquired BSL with English as a second language. The patient presented with English word finding difficulty, phonemic paraphasias, and reading and writing challenges, with BSL preserved. Intraoperatively, object naming and semantic fluency tasks were performed in English and BSL, revealing differential language maps for each modality. Post-operative assessment confirmed mild dysphasia for English with BSL preserved. These findings suggest that in hearing people who acquire a signed language as a first language, topographical organisation may differ to that of a second, spoken, language.

Theory-based implementation of an enhanced recovery protocol for cranial surgery.

OBJECTIVE: There is growing evidence for the use of enhanced recovery protocols (ERPs) in cranial surgery. As they become widespread, successful implementation of these complex interventions will become a challenge for neurosurgical teams owing to the need for multidisciplinary engagement. Here, the authors describe the novel use of an implementation framework (normalization process theory [NPT]) to promote the incorporation of a cranial surgery ERP into routine neuro-oncology practice. METHODS: A baseline audit was conducted to determine the degree of implementation of the ERP into practice. The Normalization MeAsure Development (NoMAD) questionnaire was circulated among 6 groups of stakeholders (neurosurgeons, anesthetists, intensivists, recovery nurses, preoperative assessment nurses, and neurosurgery ward staff) to examine barriers to implementation. Based on these findings, a theory-guided implementation intervention was delivered. A repeat audit and NoMAD questionnaire were conducted to assess the impact of the intervention on the uptake of the ERP. RESULTS: The baseline audit (n = 24) demonstrated limited delivery of the ERP elements. The NoMAD questionnaire (n = 32) identified 4 subconstructs of the NPT as barriers to implementation: communal specification, contextual integration, skill set workability, and relational integration. These guided an implementation intervention that included the following: 1) teamwork-focused training; 2) ERP promotion; and 3) procedure simplification. The reaudit (n = 21) demonstrated significant increases in the delivery of 5 protocol elements: scalp block (12.5% of patients before intervention vs 76.2% of patients after intervention, p < 0.00001), recommended analgesia (25.0% vs 100.0%, p < 0.00001) and antiemetics (12.5% vs 100.0%, p < 0.00001), trial without catheter (13.6% vs 88.9%, p < 0.00001), and mobilization on the 1st postoperative day (45.5% vs 94.4%, p < 0.00001). There was a significant reduction in the mean hospital length of stay from 6.3 ± 3.4 to 4.2 ± 1.7 days (p = 0.022). Two months after implementation, a repeat NoMAD survey demonstrated significant improvement in communal specification. CONCLUSIONS: Here, the authors have demonstrated the successful implementation of a cranial surgery ERP by using a systematic theory-based approach.

Usability of mixed reality in awake craniotomy planning.

PURPOSE: This study aimed to describe our institutional use of a commercially available mixed reality viewer within a multi-disciplinary planning workflow for awake craniotomy surgery and to report an assessment of its usability. MATERIALS AND METHODS: Three Tesla MRI scans, including 32-direction diffusion tensor sequences, were reconstructed with BrainLab Elements auto-segmentation software. Magic Leap mixed reality viewer headsets were registered to a shared virtual viewing space to display image reconstructions. System Usability Scale was used to assess the usability of the mixed reality system. RESULTS: The awake craniotomy planning workflow utilises the mixed reality viewer to facilitate a stepwise discussion through four progressive anatomical layers; the skin, cerebral cortex, subcortical white matter tracts and tumour with surrounding vasculature. At each stage relevant members of the multi-disciplinary team review key operative considerations, including patient positioning, cortical and subcortical speech mapping protocols and surgical approaches to the tumour.The mixed reality system was used for multi-disciplinary awake craniotomy planning in 10 consecutive procedures over a 5-month period. Ten participants (2 Anaesthetists, 5 Neurosurgical trainees, 2 Speech therapists, 1 Neuropsychologist) completed System Usability Scale assessments, reporting a mean score of 71.5. Feedback highlighted the benefit of being able to rehearse important steps in the procedure, including patient positioning and anaesthetic access and visualising the testing protocol for cortical and subcortical speech mapping. CONCLUSIONS: This study supports the use of mixed reality for multidisciplinary planning for awake craniotomy surgery, with an acceptable degree of usability of the interface. We highlight the need to consider the requirements of non-technical, non-neurosurgical team members when involving mixed reality activities.

Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson's disease.

We investigated the effects of glial cell line-derived neurotrophic factor (GDNF) in Parkinson's disease, using intermittent intraputamenal convection-enhanced delivery via a skull-mounted transcutaneous port as a novel administration paradigm to potentially afford putamen-wide therapeutic delivery. This was a single-centre, randomized, double-blind, placebo-controlled trial. Patients were 35-75 years old, had motor symptoms for 5 or more years, and presented with moderate disease severity in the OFF state [Hoehn and Yahr stage 2-3 and Unified Parkinson's Disease Rating Scale motor score (part III) (UPDRS-III) between 25 and 45] and motor fluctuations. Drug delivery devices were implanted and putamenal volume coverage was required to exceed a predefined threshold at a test infusion prior to randomization. Six pilot stage patients (randomization 2:1) and 35 primary stage patients (randomization 1:1) received bilateral intraputamenal infusions of GDNF (120 µg per putamen) or placebo every 4 weeks for 40 weeks. Efficacy analyses were based on the intention-to-treat principle and included all patients randomized. The primary outcome was the percentage change from baseline to Week 40 in the OFF state (UPDRS-III). The primary analysis was limited to primary stage patients, while further analyses included all patients from both study stages. The mean OFF state UPDRS motor score decreased by 17.3 ± 17.6% in the active group and 11.8 ± 15.8% in the placebo group (least squares mean difference: -4.9%, 95% CI: -16.9, 7.1, P = 0.41). Secondary endpoints did not show significant differences between the groups either. A post hoc analysis found nine (43%) patients in the active group but no placebo patients with a large clinically important motor improvement (≥10 points) in the OFF state (P = 0.0008). 18F-DOPA PET imaging demonstrated a significantly increased uptake throughout the putamen only in the active group, ranging from 25% (left anterior putamen; P = 0.0009) to 100% (both posterior putamina; P < 0.0001). GDNF appeared to be well tolerated and safe, and no drug-related serious adverse events were reported. The study did not meet its primary endpoint. 18F-DOPA imaging, however, suggested that intermittent convection-enhanced delivery of GDNF produced a putamen-wide tissue engagement effect, overcoming prior delivery limitations. Potential reasons for not proving clinical benefit at 40 weeks are discussed.

Deep brain stimulation: practical insights and common queries.

The number of patients with deep brain stimulation (DBS) devices implanted is increasing. Although practices vary between centres, patients are typically given training and information from their DBS nurse or clinician, as well as a comprehensive device manual and contact details for their device manufacturer. However, for the lifetime of a patient with a DBS system, most of their secondary care often occurs in a centre without a co-located DBS service. The local neurologist is often asked pragmatic questions regarding the do's and don'ts for patients with DBS systems. While a DBS centre or device manufacturer can provide advice, we thought that it will be helpful to outline the overall management of DBS for movement disorders and the approach to commonly raised questions. We describe briefly the clinical application of DBS and discuss common scenarios where there are possible compatibility issues around the device.

Non-pharmacological fatigue interventions for patients with a primary brain tumour: a scoping review protocol.

INTRODUCTION: Fatigue is the most prevalent symptom for patients with a primary brain tumour (PBT), significantly reducing quality of life and limiting daily activities. Currently, there are limited options for managing cancer-related fatigue (CRF) in patients with a PBT, using non-pharmacological methods. The objective of this scoping review is to identify current and emerging evidence in relation to non-pharmacological CRF interventions for patients with a PBT. METHODS AND ANALYSIS: Electronic databases OVID and EBSCO platforms: MEDLINE, EMBASE and CINAHL will be searched. In addition, PROSPERO, The Cochrane Library and ISI Web of Science will be searched. Trials registries CENTRAL and the International Clinical Trials Registry platform will also be searched for ongoing research. INCLUSION CRITERIA: studies from 2006 onwards, primary research on non-pharmacological interventions in patients with a PBT (>18 years). A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram will be utilised to summarise the screening process and results.Quantitative data will be analysed descriptively, while content analysis will be used for qualitative data.Findings will map the existing and emerging evidence on non-pharmacological interventions for CRF in patients with PBTs. This will provide insights into the extent and nature of the evidence in this evolving field, identifying gaps in knowledge and research priorities, and guide further investigations in this area. ETHICS AND DISSEMINATION: Ethical approval is not required for this scoping review. Findings will be disseminated via relevant peer-reviewed journals, PhD thesis, conference presentations, and shared with relevant charities and health professionals.

Anaesthetic complications in pigs undergoing MRI guided convection enhanced drug delivery to the brain: a case series.

OBSERVATIONS: A total of 13 intracerebral infusions were performed at approximately 1 month intervals in three NIH miniature pigs over the age range of 31-59 weeks. Pigs received azaperone and ketamine premedication to allow venous cannulation and propofol induction of anaesthesia. Anaesthesia was maintained with isoflurane throughout cranial surgery and MRI scanning. Physiological monitoring during surgery consisted of blood pressure, pulse, temperature and oxygen saturation monitoring, ECG and capnography. Analgesia consisted of meloxicam and morphine. However, during MRI scanning blood pressure and ECG monitoring had to be discontinued. Anaesthetized pigs underwent intermittent intraputamenal convection enhanced delivery (CED) of gadolinium with real-time magnetic resonance imaging. Progressive tachycardia was consistently observed in all pigs during CED with a mean ± SD maximum increase of 41 ± 22 beats minute(-1) from a baseline heart rate of 96 ± 9 minute(-1) . The heart rate remained elevated until recovery. A mean reduction in body temperature of 2.8 ± 0.6 °C from the start of anaesthesia was also observed during the period of MRI scanning. All pigs recovered from anaesthesia smoothly and heart rates returned to normal during the recovery period. CONCLUSIONS: Hypothermia is common in pigs undergoing this sedation and anaesthesia protocol. Convection enhanced delivery of drugs in healthy anaesthetized pigs may result in tachycardia.

Two Hundred Twenty-Six Consecutive Deep Brain Stimulation Electrodes Placed Using an "Asleep" Technique and the Neuro|MateTM Robot for the Treatment of Movement Disorders.

BACKGROUND: Robotics in neurosurgery has demonstrated widening indications and rapid growth in recent years. Robotic precision and reproducibility are especially pertinent to the field of functional neurosurgery. Deep brain stimulation (DBS) requires accurate placement of electrodes in order to maximize efficacy and minimize side effects. In addition, asleep techniques demand clear target visualization and immediate on-table verification of accuracy. OBJECTIVE: To describe the surgical technique of asleep DBS surgery using the Neuro|MateTM Robot (Renishaw plc, Wotton-under-Edge, United Kingdom) and examine the accuracy of DBS lead placement in the subthalamic nucleus (STN) for the treatment of movement disorders. METHODS: A single-center retrospective review of 113 patients who underwent bilateral STN/Zona Incerta electrode placement was performed. Accuracy of implantation was assessed using 5 measurements, Euclidian distance, radial error, depth error, angular error, and shift error. RESULTS: A total of 226 planned vs actual electrode placements were analyzed. The mean 3-dimensional vector error calculated for 226 trajectories was 0.78 +/- 0.37 mm. The mean radial displacement off planned trajectory was 0.6 +/- 0.33 mm. The mean depth error, angular error, and shift error was 0.4 +/- 0.35 mm, 0.4 degrees, and 0.3 mm, respectively. CONCLUSION: This report details our institution's method for DBS lead placement in patients under general anaesthesia using anatomical targeting without microelectrode recordings or intraoperative test stimulation for the treatment of movement disorders. This is the largest reported dataset of accuracy results in DBS surgery performed asleep. This novel robot-assisted operative technique results in sub-millimeter accuracy in DBS electrode placement.

Clinical Outcome of "Asleep" Deep Brain Stimulation for Parkinson Disease Using Robot-Assisted Delivery and Anatomic Targeting of the Subthalamic Nucleus: A Series of 152 Patients.

BACKGROUND: Recent advances in methods used for deep brain stimulation (DBS) include subthalamic nucleus electrode implantation in the "asleep" patient without the traditional use of microelectrode recordings or intraoperative test stimulation. OBJECTIVE: To examine the clinical outcome of patients who have undergone "asleep" DBS for the treatment of Parkinson disease using robot-assisted electrode delivery. METHODS: This is a retrospective review of clinical outcomes of 152 consecutive patients. Their outcomes at 1 yr postimplantation are reported; these include Unified Parkinson's Disease Rating Scale (UPDRS) assessment, Tinetti Mobility Test, Parkinson's Disease Questionnaire (PDQ)-39 quality of life assessment, Mattis Dementia Rating Scale, Beck Depression Inventory, and Beck Anxiety. We also report on a new parietal trajectory for electrode implantation. RESULTS: A total of 152 patients underwent assessment at 1 yr. UPDRS III improved from 39 to 20.5 (47%, P < .001). The total UPDRS score improved from 67.6 to 36.4 (46%, P < .001). UPDRS II scores improved from 18.9 to 10.5 (44%, P < .001) and UPDRS IV scores improved from 7.1 to 3.6 (49%, P < .001). There was a significant reduction in levodopa equivalent daily dose after surgery (mean: 35%, P < .001). PDQ-39 summary index improved by a mean of 7.1 points. There was no significant difference found in clinical outcomes between the frontal and parietal approaches. CONCLUSION: "Asleep" robot-assisted DBS of the subthalamic nucleus demonstrates comparable outcomes with traditional techniques in the treatment of Parkinson disease.

Impact of COVID-19 pandemic on surgical neuro-oncology multi-disciplinary team decision making: a national survey (COVID-CNSMDT Study).

OBJECTIVES: Pressures on healthcare systems due to COVID-19 has impacted patients without COVID-19 with surgery disproportionally affected. This study aims to understand the impact on the initial management of patients with brain tumours by measuring changes to normal multidisciplinary team (MDT) decision making. DESIGN: A prospective survey performed in UK neurosurgical units performed from 23 March 2020 until 24 April 2020. SETTING: Regional neurosurgical units outside London (as the pandemic was more advanced at time of study). PARTICIPANTS: Representatives from all units were invited to collect data on new patients discussed at their MDT meetings during the study period. Each unit decided if management decision for each patient had changed due to COVID-19. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome measures included number of patients where the decision to undergo surgery changed compared with standard management usually offered by that MDT. Secondary outcome measures included changes in surgical extent, numbers referred to MDT, number of patients denied surgery not receiving any treatment and reasons for any variation across the UK. RESULTS: 18 units (75%) provided information from 80 MDT meetings that discussed 1221 patients. 10.7% of patients had their management changed-the majority (68%) did not undergo surgery and more than half of this group not undergoing surgery had no active treatment. There was marked variation across the UK (0%-28% change in management). Units that did not change management could maintain capacity with dedicated oncology lists. Low volume units were less affected. CONCLUSION: COVID-19 has had an impact on patients requiring surgery for malignant brain tumours, with patients receiving different treatments-most commonly not receiving surgery or any treatment at all. The variations show dedicated cancer operating lists may mitigate these pressures. STUDY REGISTRATION: This study was registered with the Royal College of Surgeons of England's COVID-19 Research Group (https://www.rcseng.ac.uk/coronavirus/rcs-covid-research-group/).

Extended Treatment with Glial Cell Line-Derived Neurotrophic Factor in Parkinson's Disease.

BACKGROUND: Intraputamenal glial cell line-derived neurotrophic factor (GDNF), administered every 4 weeks to patients with moderately advanced Parkinson's disease, did not show significant clinical improvements against placebo at 40 weeks, although it significantly increased [18F]DOPA uptake throughout the entire putamen. OBJECTIVE: This open-label extension study explored the effects of continued (prior GDNF patients) or new (prior placebo patients) exposure to GDNF for another 40 weeks. METHODS: Using the infusion protocol of the parent study, all patients received GDNF without disclosing prior treatment allocations (GDNF or placebo). The primary outcome was the percentage change from baseline to Week 80 in the OFF state Unified Parkinson's Disease Rating Scale (UPDRS) motor score. RESULTS: All 41 parent study participants were enrolled. The primary outcome decreased by 26.7±20.7% in patients on GDNF for 80 weeks (GDNF/GDNF; N = 21) and 27.6±23.6% in patients on placebo for 40 weeks followed by GDNF for 40 weeks (placebo/GDNF, N = 20; least squares mean difference: 0.4%, 95% CI: -13.9, 14.6, p = 0.96). Secondary endpoints did not show significant differences between the groups at Week 80 either. Prespecified comparisons between GDNF/GDNF at Week 80 and placebo/GDNF at Week 40 showed significant differences for mean OFF state UPDRS motor (-9.6±6.7 vs. -3.8±4.2 points, p = 0.0108) and activities of daily living score (-6.9±5.5 vs. -1.0±3.7 points, p = 0.0003). No treatment-emergent safety concerns were identified. CONCLUSIONS: The aggregate study results, from the parent and open-label extension suggest that future testing with GDNF will likely require an 80- rather than a 40-week randomized treatment period and/or a higher dose.

Drug Delivery for Movement Disorders.

There has been substantial research interest in delivering therapeutic neurotrophic factors directly to the brain for the treatment of Parkinson's Disease (PD) and other movement disorders. Direct infusion of glial cell-line derived neurotrophic factor has been investigated in both pre-clinical models and clinical trials. In this chapter we discuss past and present research investigating the potential of direct drug delivery to the brain for the treatment of PD and other movement disorders.

Combined use of CDK4/6 and mTOR inhibitors induce synergistic growth arrest of diffuse intrinsic pontine glioma cells via mutual downregulation of mTORC1 activity.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a lethal type of pediatric brain tumor that is resistant to conventional chemotherapies. Palbociclib is a putative novel DIPG treatment that restricts the proliferation of rapidly dividing cancer cells via selective inhibition of cyclin-dependent kinase (CDK) 4 and CDK6. However, implementing palbociclib as a monotherapy for DIPG is unfeasible, as CDK4/6 inhibitor resistance is commonplace and palbociclib does not readily cross the blood-brain barrier (BBB) or persist in the central nervous system. To inhibit the growth of DIPG cells, we aimed to use palbociclib in combination with the rapamycin analog temsirolimus, which is known to ameliorate resistance to CDK4/6 inhibitors and inhibit BBB efflux. MATERIALS AND METHODS: We tested palbociclib and temsirolimus in three patient-derived DIPG cell lines. The expression profiles of key proteins in the CDK4/6 and mammalian target of rapamycin (mTOR) signaling pathways were assessed, respectively, to determine feasibility against DIPG. Moreover, we investigated effects on cell viability and examined in vivo drug toxicity. RESULTS: Immunoblot analyses revealed palbociclib and temsirolimus inhibited CDK4/6 and mTOR signaling through canonical perturbation of phosphorylation of the retinoblastoma (RB) and mTOR proteins, respectively; however, we observed noncanonical downregulation of mTOR by palbociclib. We demonstrated that palbociclib and temsirolimus inhibited cell proliferation in all three DIPG cell lines, acting synergistically in combination to further restrict cell growth. Flow cytometric analyses revealed both drugs caused G1 cell cycle arrest, and clonogenic assays showed irreversible effects on cell proliferation. Palbociclib did not elicit neurotoxicity in primary cultures of normal rat hippocampi or when infused into rat brains. CONCLUSION: These data illustrate the in vitro antiproliferative effects of CDK4/6 and mTOR inhibitors in DIPG cells. Direct infusion of palbociclib into the brain, in combination with systemic delivery of temsirolimus, represents a promising new approach to developing a much-needed treatment for DIPG.

Maximising coverage of brain structures using controlled reflux, convection-enhanced delivery and the recessed step catheter.

BACKGROUND: The design and use of convection-enhanced delivery catheters remains an active field as clinical trials have highlighted suboptimal distribution as a contributory factor to the failure of those studies. Recent studies indicate limitations and challenges in achieving target coverage using conventional point source delivery. NEW METHOD: The recessed step catheter(RSC), developed by this group, does not function as a point source delivery device, but instead uses 'controlled reflux' of the infusate to a flow inhibiting recess feature. Here we investigate a range of clinically useful step lengths in agarose gel and investigate proof-of-principle in vivo(n = 5). Infusion morphology was characterised in terms of length, width and distribution volume over a range of flow rates. RESULTS: For a fixed infusion volume, increases in catheter step length strongly correlated with increases in the length and volume of distribution (r>0.90, p < 0.001) whilst there were small reductions in the width of distribution (r<-0.62, p < 0.001). Step lengths below 6 mm produced spherical distributions while steps above 12 mm produced elongated distributions. Increasing peak flow rates resulted in significant reductions in distribution volume at each step length, and an increased risk of reflux beyond the step. Modifications to the infusion morphology using changes in step length were confirmed in vivo. CONCLUSIONS: The combination of the recessed step and the ability to adjust the step length with this catheter design make it highly suitable for tailoring the distribution volume of the infusate to meet specific morphological target volumes in the brain.

Single Electrode Deep Brain Stimulation with Dual Targeting at Dual Frequency for the Treatment of Chronic Pain: A Case Series and Review of the Literature.

Deep Brain Stimulation (DBS) has been used to target many deep brain structures for the treatment of chronic pain. The periaqueductal grey and periventricular grey (PAG/PVG) is an effective target but results are variable, sometimes short-lived or subject to tolerance. The centromedian intra-laminar parafascicular complex (CMPf) modulates medial pain pathways and CMPf DBS may address the affective aspects of pain perception. Stimulation of multiple deep brain targets may offer a strategy to optimize management of patients with complex pain symptomatology. However, previous attempts to stimulate multiple targets requires multiple trajectories and considerable expense. Using a single electrode to stimulate multiple targets would help overcome these challenges. A pre-requisite of such a technique is the ability to use different stimulation parameters at different contacts simultaneously on the same electrode. We describe a novel technique in 3 patients with chronic pain syndromes for whom conventional medical and/or neuromodulation therapy had failed using a single electrode technique to stimulate PVG/PAG and CMPf at dual frequencies.

Repurposing the anti-epileptic drug sodium valproate as an adjuvant treatment for diffuse intrinsic pontine glioma.

Targeting epigenetic changes in diffuse intrinsic pontine glioma (DIPG) may provide a novel treatment option for patients. This report demonstrates that sodium valproate, a histone deacetylase inhibitor (HDACi), can increase the cytotoxicity of carboplatin in an additive and synergistic manner in DIPG cells in vitro. Sodium valproate causes a dose-dependent decrease in DIPG cell viability in three independent ex vivo cell lines. Furthermore, sodium valproate caused an increase in acetylation of histone H3. Changes in cell viability were consistent with an induction of apoptosis in DIPG cells in vitro, determined by flow cytometric analysis of Annexin V staining and assessment of apoptotic markers by western blotting. Subsequently, immunofluorescent staining of neuronal and glial markers was used to determine toxicity in normal rat hippocampal cells. Pre-treatment of cells with sodium valproate enhanced the cytotoxic effects of carboplatin, in three DIPG cell lines tested. These results demonstrate that sodium valproate causes increased histone H3 acetylation indicative of HDAC inhibition, which is inversely correlated with a reduction in cell viability. Cell viability is reduced through an induction of apoptosis in DIPG cells. Sodium valproate potentiates carboplatin cytotoxicity and prompts further work to define the mechanism responsible for the synergy between these two drugs and determine in vivo efficacy. These findings support the use of sodium valproate as an adjuvant treatment for DIPG.

Chronic, intermittent convection-enhanced delivery devices.

BACKGROUND: Intraparenchymal convection-enhanced delivery (CED) of therapeutics directly into the brain has long been endorsed as a medium through which meaningful concentrations of drug can be administered to patients, bypassing the blood brain barrier. The translation of the technology to clinic has been hindered by poor distribution not previously observed in smaller pre-clinical models. In part this was due to the larger volumes of target structures found in humans but principally the poor outcome was linked to reflux (backflow) of infusate proximally along the catheter track. Over the past 10 years, improvements have been made to the technology in the field which has led to a small number of commercially available devices containing reflux inhibiting features. NEW METHOD: While these devices are currently suitable for acute or short term use, several indications would benefit from longer term repeated, intermittent administration of therapeutics (Parkinson's, Alzheimer's, Amyotrophic lateral sclerosis, Brain tumours such as Glioblastoma Multiforme (GBM) and Diffuse intrinsic Pontine Glioma (DIPG), etc.). RESULTS: Despite the need for a chronically accessible platform for such indications, limited experience exists in this part of the field. COMPARISON WITH EXISTING METHOD(S): At the time of writing no commercially available clinical platform, indicated for chronic, intermittent or continuous delivery to the brain exists. CONCLUSIONS: Here we review the improvements that have been made to CED devices over recent years and current state of the art for chronic infusion systems.

A novel implantable catheter system with transcutaneous port for intermittent convection-enhanced delivery of carboplatin for recurrent glioblastoma.

CONTEXT: Inadequate penetration of the blood-brain barrier (BBB) by systemically administered chemotherapies including carboplatin is implicated in their failure to improve prognosis for patients with glioblastoma. Convection-enhanced delivery (CED) of carboplatin has the potential to improve outcomes by facilitating bypass of the BBB. OBJECTIVE: We report the first use of an implantable CED system incorporating a novel transcutaneous bone-anchored port (TBAP) for intermittent CED of carboplatin in a patient with recurrent glioblastoma. MATERIALS AND METHODS: The CED catheter system was implanted using a robot-assisted surgical method. Catheter targeting accuracy was verified by performing intra-operative O-arm imaging. The TBAP was implanted using a skin-flap dermatome technique modeled on bone-anchored hearing aid surgery. Repeated infusions were performed by attaching a needle administration set to the TBAP. Drug distribution was monitored with serial real-time T2-weighted magnetic resonance imaging (MRI). RESULTS: All catheters were implanted to within 1.5 mm of their planned target. Intermittent infusions of carboplatin were performed on three consecutive days and repeated after one month without the need for further surgical intervention. Infused volumes of 27.9 ml per day were well tolerated, with the exception of a single seizure episode. Follow-up MRI at eight weeks demonstrated a significant reduction in the volume of tumor enhancement from 42.6 ml to 24.6 ml, and was associated with stability of the patient's clinical condition. CONCLUSION: Reduction in the volume of tumor enhancement indicates that intermittent CED of carboplatin has the potential to improve outcomes in glioblastoma. The novel technology described in this report make intermittent CED infusion regimes an achievable treatment strategy.

Convection-Enhanced Delivery of Carboplatin PLGA Nanoparticles for the Treatment of Glioblastoma.

We currently use Convection-Enhanced Delivery (CED) of the platinum-based drug, carboplatin as a novel treatment strategy for high grade glioblastoma in adults and children. Although initial results show promise, carboplatin is not specifically toxic to tumour cells and has been associated with neurotoxicity at high infused concentrations in pre-clinical studies. Our treatment strategy requires intermittent infusions due to rapid clearance of carboplatin from the brain. In this study, carboplatin was encapsulated in lactic acid-glycolic acid copolymer (PLGA) to develop a novel drug delivery system. Neuronal and tumour cytotoxicity were assessed in primary neuronal and glioblastoma cell cultures. Distribution, tissue clearance and toxicity of carboplatin nanoparticles following CED was assessed in rat and porcine models. Carboplatin nanoparticles conferred greater tumour cytotoxicity, reduced neuronal toxicity and prolonged tissue half-life. In conclusion, this drug delivery system has the potential to improve the prognosis for patients with glioblastomas.

Convection-enhanced drug delivery to the brain: therapeutic potential and neuropathological considerations.

Convection-enhanced delivery (CED) describes a direct method of drug delivery to the brain through intraparenchymal microcatheters. By establishing a pressure gradient at the tip of the infusion catheter in order to exploit bulk flow through the interstitial spaces of the brain, CED offers a number of advantages over conventional drug delivery methods-bypass of the blood-brain barrier, targeted distribution through large brain volumes and minimization of systemic side effects. Despite showing early promise, CED is yet to fulfill its potential as a mainstream strategy for the treatment of neurological disease. Substantial research effort has been dedicated to optimize the technology for CED and identify the parameters, which govern successful drug distribution. It seems likely that successful clinical translation of CED will depend on suitable catheter technology being used in combination with drugs with optimal physicochemical characteristics, and on neuropathological analysis in appropriate preclinical models. In this review, we consider the factors most likely to influence the success or failure of CED, and review its application to the treatment of high-grade glioma, Parkinson's disease (PD) and Alzheimer's disease (AD).