Glial cell-derived neurotrophic factor (GDNF), and the neurotrophin nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important for the survival, maintenance and regeneration ...of specific neuronal populations in the adult brain. Depletion of these neurotrophic factors has been linked with disease pathology and symptoms, and replacement strategies are considered as potential therapeutics for neurodegenerative diseases such as Parkinson's, Alzheimer's and Huntington's diseases. GDNF administration has recently been shown to be an effective treatment for Parkinson's disease, with clinical trials currently in progress. Trials with NGF for Alzheimer's disease are ongoing, with some degree of success. Preclinical results using BDNF also show much promise, although there are accompanying difficulties. Ultimately, the administration of a therapy involving proteins in the brain has inherent problems. Because of the blood-brain-barrier, the protein must be infused directly, produced by viral constructs, secreted from implanted protein-secreting cells or actively transported across the brain. An alternative to this is the use of a small molecule agonist, a modulator or enhancer targeting the associated receptors. We evaluate these neurotrophic factors as potential short or long-term treatments, weighing up preclinical and clinical results with the possible effects on the underlying neurodegenerative process.
Trials of GDNF in Parkinson's disease have yielded inconsistent results. In a randomised controlled trial, Whone et al. administer GDNF using a paradigm designed to optimize delivery to the putamen. ...18FDOPA PET reveals putamen-wide uptake, but GDNF does not differ from placebo in its effects on motor function.
Abstract
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.
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).
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•State of the art review of catheter designs for convection-enhanced delivery.•Analysis of the design features, materials and methods of use which could be applied to chronic intermittent drug ...delivery systems and clinical trials to minimise risk of trial failure and opportunities to optimise intraparenchymal distributions.
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.
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.).
Despite the need for a chronically accessible platform for such indications, limited experience exists in this part of the field.
At the time of writing no commercially available clinical platform, indicated for chronic, intermittent or continuous delivery to the brain exists.
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.
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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.
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.
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.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
•The recessed step CED catheter can be used to optimise infusions in neurodegenerative or neuro-oncological indications.•The variable step length can be used to control the shape of the distribution ...volume to match the target morphology.•Novel surgical trajectories could be employed to maximise coverage of structures such as the striatum, thalamus or pons.
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.
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.
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.
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.
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.
A prospective survey performed in UK neurosurgical units performed from 23 March 2020 until 24 April 2020.
Regional neurosurgical units outside London (as the pandemic was more advanced at time of study).
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 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.
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.
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.
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/).
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