Perspective: Vagal nerve stimulation in the treatment of new-onset refractory status epilepticus.

Introduction: Resistance to drug therapy is a major hurdle in new-onset refractory status epilepticus (NORSE) treatment and there is urgent need to develop new treatment approaches. Non-drug approaches such as neuromodulation offer significant benefits and should be investigated as new adjunct treatment modalities. An important unanswered question is whether desynchronizing networks by vagal nerve stimulation (VNS) may improve seizure control in NORSE patients. Main text: We present a summary of published NORSE cases treated with VNS and our own data, discuss possible mechanisms of action, review VNS implantation timing, stimulation setting titration protocols and outcomes. Further, we propose avenues for future research. Discussion: We advocate for consideration of VNS for NORSE both in early and late stages of the presentation and hypothesize a possible additional benefit from implantation in the acute phase of the disease. This should be pursued in the context of a clinical trial, harmonizing inclusion criteria, accuracy of documentation and treatment protocols. A study planned within our UK-wide NORSE-UK network will answer the question if VNS may confer benefits in aborting unremitting status epilepticus, modulate ictogenesis and reduce long-term chronic seizure burden.

Safe and effective implantation and use of vagal nerve stimulation in new-onset refractory status epilepticus in early pregnancy: a case report.

Introduction: The management of new-onset refractory status epilepticus (NORSE) in pregnancy may be complicated by anti-seizure medication (ASM) polytherapy-associated teratogenicity. We aim to demonstrate the safety and efficacy of vagal nerve stimulation (VNS) in a pregnant patient presenting with NORSE. Case description: A 30-year old female, at 5-weeks' gestation presented with drug-refractory myoclonic status epilepticus, responsive only to high levels of anesthetic agents. The severity of seizures did not allow extubation, and the patient remained ventilated and sedated. VNS was implanted 26 days after seizure onset. The immediate post-operative output was 0.25 mA, which was rapidly titrated up to 0.5 mA the next morning, and to 0.75 mA that afternoon. This was further increased to 1.0 mA on 3rd day post-operation, and to 1.25 mA 7 days post-op. Myoclonic jerks diminished significantly 7 days post-op, allowing extubation. Twenty days after VNS implantation, no myoclonic jerks were observed. There was also a notable neurological improvement including increased alertness and mobility, and ability to obey commands. Drug overdose was subsequently found to be the most likely etiology of her NORSE. An early pregnancy assessment 17 days after VNS implantation showed a normally sited pregnancy, normal fetal heart activity and crown-rump length. The patient remained seizure free, gained functional independence and delivered a premature but otherwise healthy baby at 33 weeks' gestation. Conclusion: NORSE is challenging to manage, further compounded in pregnancy due to the teratogenicity of ASMs and ASM polytherapy. This is the first case-study to report the safe implantation and use of VNS during the first trimester of pregnancy for the management of NORSE.

Neuromate® robot-assisted ventricular catheter insertion.

BACKGROUND AND IMPORTANCE: Insertion of ventricular catheters into small ventricles may require image guidance. Several options exist, including ultrasound guidance, frameless, and frame-based stereotactic approaches. There is no literature on management options when conventional image guidance fails to cannulate the ventricle. The accuracy of the robotic arm is well established in functional and epilepsy surgery. We report the first case using the Neuromate® robot for the placement of a shunt ventricular catheter into the lateral ventricle after a failed attempt with a more commonly used frameless electromagnetic navigation system. CLINICAL PRESENTATION: A 30-year-old man had twice previously undergone foramen magnum decompression for a Chiari 1 malformation. He subsequently developed a significant cervical syrinx with clinical deterioration and a decision was made to place a ventriculoperitoneal shunt. As the ventricles were small, frameless electromagnetic navigation was used but the ventricle could not be cannulated. The Neuromate® robot was subsequently used to place the ventricular catheter successfully. CONCLUSION: Neuromate® robot-assisted ventricular catheter placement may be considered when difficulty is experienced with more commonly used image guidance techniques.

Probabilistic mapping of deep brain stimulation in childhood dystonia.

OBJECTIVES: In adults with dystonia Probabilistic Stimulation Mapping (PSM) has identified putative "sweet spots" for stimulation. We aimed to apply PSM to a cohort of Children and Young People (CYP) following DBS surgery. METHODS: Pre-operative MRI and post-operative CT images were co-registered for 52 CYP undergoing bilateral pallidal DBS (n = 31 genetic/idiopathic dystonia, and n = 21 Cerebral Palsy (CP)). DBS electrodes (n = 104) were automatically detected, and Volumes of Tissue Activation (VTA) derived from individual patient stimulation settings. VTAs were normalised to the MNI105 space, weighted by percentage improvement in Burke-Fahn-Marsden Dystonia Rating scale (BFMDRS) at one-year post surgery and mean improvement was calculated for each voxel. RESULTS: For the genetic/idiopathic dystonia group, BFMDRS improvement was associated with stimulation across a broad volume of the GPi. A spatial clustering of the upper 25th percentile of voxels corresponded with a more delineated volume within the posterior ventrolateral GPi. The MNI coordinates of the centroid of this volume (X = -23.0, Y = -10.5 and Z = -3.5) were posterior and superior to the typical target for electrode placement. Volume of VTA overlap with a previously published "sweet spots" correlated with improvement following surgery. In contrast, there was minimal BFMDRS improvement for the CP group, no spatial clustering of efficacious clusters and a correlation between established "sweet spots" could not be established. CONCLUSIONS: PSM in CYP with genetic/idiopathic dystonia suggests the presence of a "sweet spot" for electrode placement within the GPi, consistent with previous studies. Further work is required to identify and validate putative "sweet spots" across different cohorts of patients.

Long-term outcome of vagus nerve stimulation for drug-resistant epilepsy using continuous assessment, with a note on mortality.

PURPOSE: To examine the outcome of vagus nerve stimulation (VNS) for drug-resistant epilepsy using data from a National Health Service VNS clinic. METHODS: Clinical records of patients implanted with VNS for epilepsy between1995 and 2010 were examined. Patients were selected for study who had at least one year of therapeutic stimulation (minimum 1 mA stimulator current) and follow-up by our service with analysable electronic records, providing continuous assessment of seizure control during available follow-up. Seizure status at each attendance was assessed and graded 1-4 (1=seizure free or <5 seizures/year; 2 =≥50%reduction in seizure frequency; 3=<50% reduction; 4=no improvement compared to baseline). Responders were those whose grades improved consistently (Grades 1,2 and 3). RESULTS: Of 464 patients, 171 fulfilled the inclusion criteria and were divided into three groups: a) Responders (n = 81); b) non-responders (n = 80) and c) others (n = 10), the latter showing a late step-wise change (six improved; four deteriorated). After initial ramping up of current, groups were very stable over subsequent periods varying from one to 12 years (median 3.8 years). Sixteen patients died, 10 of non-epilepsy causes with 6 epilepsy-related deaths. There was a significant relation between epilepsy-related deaths and response (p < 0.00001). Patients with longer time as non-responders had more likelihood of suffering an epilepsy death than responders, though numbers were small. CONCLUSION: This study shows that meaningful data can be obtained retrospectively from routine clinic records. In this cohort about half of patients treated with VNS responded and the response generally remaining stable over time.

Targeting accuracy of robot-assisted deep brain stimulation surgery in childhood-onset dystonia: a single-center prospective cohort analysis of 45 consecutive cases.

OBJECTIVE: Deep brain stimulation (DBS) is an established treatment for pediatric dystonia. The accuracy of electrode implantation is multifactorial and remains a challenge in this age group, mainly due to smaller anatomical targets in very young patients compared to adults, and also due to anatomical abnormalities frequently associated with some etiologies of dystonia. Data on the accuracy of robot-assisted DBS surgery in children are limited. The aim of the current paper was to assess the accuracy of robot-assisted implantation of DBS leads in a series of patients with childhood-onset dystonia. METHODS: Forty-five children with dystonia undergoing implantation of DBS leads under general anesthesia between 2017 and 2019 were included. Robot-assisted stereotactic implantation of the DBS leads was performed. The final position of the electrodes was verified with an intraoperative 3D scanner (O-arm). Coordinates of the planned electrode target and actual electrode position were obtained and compared, looking at the radial error, depth error, absolute error, and directional error, as well as the euclidean distance. Functional assessment data prospectively collected by a multidisciplinary pediatric complex motor disorders team were analyzed with regard to motor skills, individualized goal achievement, and patients' and caregivers' expectations. RESULTS: A total of 90 DBS electrodes were implanted and 48.5% of the patients were female. The mean age was 11.0 ± 0.6 years (range 3-18 years). All patients received bilateral DBS electrodes into the globus pallidus internus. The median absolute errors in x-, y-, and z-axes were 0.85 mm (range 0.00-3.25 mm), 0.75 mm (range 0.05-2.45 mm), and 0.75 mm (range 0.00-3.50 mm), respectively. The median euclidean distance from the target to the actual electrode position was 1.69 ± 0.92 mm, and the median radial error was 1.21 ± 0.79. The robot-assisted technique was easily integrated into the authors' surgical practice, improving accuracy and efficiency, and reducing surgical time significantly along the learning curve. No major perioperative complications occurred. CONCLUSIONS: Robot-assisted stereotactic implantation of DBS electrodes in the pediatric age group is a safe and accurate surgical method. Greater accuracy was present in this cohort in comparison to previous studies in which conventional stereotactic frame-based techniques were used. Robotic DBS surgery and neuroradiological advances may result in further improvement in surgical targeting and, consequently, in better clinical outcome in the pediatric population.

Acute bilateral foot drop with or without cauda equina syndrome-a case series.

INTRODUCTION: Isolated acute bilateral foot drop due to degenerative spine disease is an extremely rare neurosurgical presentation, whilst the literature is rich with accounts of chronic bilateral foot drop occurring as a sequela of systemic illnesses. We present, to our knowledge, the largest case series of acute bilateral foot drop, with trauma and relevant systemic illness excluded. METHODS: Data from three different centres had been collected at the time of historic treatment, and records were subsequently reviewed retrospectively, documenting the clinical presentation, radiological level of compression, timing of surgery, and degree of neurological recovery. RESULTS: Seven patients are presented. The mean age at presentation was 52.1 years (range 41-66). All patients but one were male. All had a painful radiculopathic presentation. Relevant discopathy was observed from L2/3 to L5/S1, the commonest level being L3/4. Five were treated within 24 h of presentation, and two within 48 h. Three had concomitant cauda equina syndrome; of these, the first two made a full motor recovery, one by 6 weeks follow-up and the second on the same-day post-op evaluation. Overall, five out of seven cases had full resolution of their ankle dorsiflexion pareses. One patient with 1/5 power has not improved. Another with 1/5 weakness improved to normal on the one side and to 3/5 on the other. CONCLUSION: When bilateral foot drop occurs acutely, we encourage the consideration of degenerative spinal disease. Relevant discopathy was observed from L2/3 to L5/S1; aberrant innervation may be at play. Cauda equina syndrome is not necessarily associated with acute bilateral foot drop. The prognosis seems to be pretty good with respect to recovery of the foot drop, especially if partial at presentation and if treated within 48 h.

Inhibition of Invasion by Polyphenols from Citrus Fruit and Berries in Human Malignant Glioma Cells In Vitro.

BACKGROUND/AIM: The outlook for patients with high grade glioma (HGG) remains dismal. Hence, attention has focused on numerous innovative treatments. Our group has proposed a strategy on the use of a combination of polyphenols, as anti-invasive agents for the management of these neoplasms. MATERIALS AND METHODS: The aim of this study was to evaluate the in vitro effects of citrus flavonoids (tangeretin, nobiletin, naringin and limonin) and berry extracts (chokeberry, elderberry and bilberry) on selected mediators of invasion in 2 HGG cell cultures. RESULTS: The IC50 values could only be determined for tangeretin and chokeberry extract. The rest were non-functional in this context. Immunocytochemistry and flow cytometry results showed that chokeberry extract was most effective in down-regulating the expression of CD44. Similarly, RT-PCR data supported its ability to reduce gene expression of MMP-14 and EGFR. 2D invasion assays confirmed that inhibition is greater with chokeberry extract. CONCLUSION: Both polyphenols have anti-invasive potential but chokeberry extract is a stronger agent for glioma management.

O-Arm Stereotactic Imaging in Deep Brain Stimulation Surgery Workflow: A Utility and Cost-Effectiveness Analysis.

INTRODUCTION: Deep brain stimulation (DBS) surgery is an established treatment for movement disorders. Advances in neuroimaging techniques have resulted in improved targeting accuracy that may improve clinical outcomes. This study aimed to evaluate the safety and feasibility of using the Medtronic O-arm device for the acquisition of intraoperative stereotactic imaging, targeting, and localization of DBS electrodes compared with standard stereotactic MRI or computed tomography (CT). METHODS: Patients were recruited prospectively into the study. Routine frame-based stereotactic DBS surgery was performed. Intraoperative imaging was used to facilitate and verify the accurate placement of the intracranial electrodes. The acquisition of coordinates and verification of the position of the electrodes using the O-arm were evaluated and compared with conventional stereotactic MRI or CT. Additionally, a systematic review of the literature on the use of intraoperative imaging in DBS surgery was performed. RESULTS: Eighty patients were included. The indications for DBS surgery were dystonia, Parkinson's disease, essential tremor, and epilepsy. The globus pallidus internus was the most commonly targeted region (43.7%), followed by the subthalamic nucleus (35%). Stereotactic O-arm imaging reduced the overall surgical time by 68 min, reduced the length of time of acquisition of stereotactic images by 77%, reduced patient exposure to ionizing radiation by 24.2%, significantly reduced operating room (OR) costs per procedure by 31%, and increased the OR and neuroradiology suite availability. CONCLUSIONS: The use of the O-arm in DBS surgery workflow significantly reduced the duration of image acquisition, the exposure to ionizing radiation, and costs when compared with standard stereotactic MRI or CT, without reducing accuracy.

Neurosurgery and coronavirus: impact and challenges-lessons learnt from the first wave of a global pandemic.

INTRODUCTION AND OBJECTIVES: The novel severe acute respiratory syndrome coronavirus 2 (COVID-19) pandemic has had drastic effects on global healthcare with the UK amongst the countries most severely impacted. The aim of this study was to examine how COVID-19 challenged the neurosurgical delivery of care in a busy tertiary unit serving a socio-economically diverse population. METHODS: A prospective single-centre cohort study including all patients referred to the acute neurosurgical service or the subspecialty multidisciplinary teams (MDT) as well as all emergency and elective admissions during COVID-19 (18th March 2020-15th May 2020) compared to pre-COVID-19 (18th of January 2020-17th March 2020). Data on demographics, diagnosis, operation, and treatment recommendation/outcome were collected and analysed. RESULTS: Overall, there was a reduction in neurosurgical emergency referrals by 33.6% and operations by 55.6% during the course of COVID-19. There was a significant increase in the proportion of emergency operations performed during COVID-19 (75.2% of total, n=155) when compared to pre-COVID-19 (n = 198, 43.7% of total, p < 0.00001). In contrast to other published series, the 30-day perioperative mortality remained low (2.0%) with the majority of post-operative COVID-19-infected patients (n = 13) having underlying medical co-morbidities and/or suffering from post-operative complications. CONCLUSION: The capacity to safely treat patients requiring urgent or emergency neurosurgical care was maintained at all times. Strategies adopted to enable this included proactively approaching the referrers to maintain lines of communications, incorporating modern technology to run clinics and MDTs, restructuring patient pathways/facilities, and initiating the delivery of NHS care within private sector hospitals. Through this multi-modal approach we were able to minimize service disruptions, the complications, and mortality.

Deep Brain Stimulation of the Internal Pallidum in Lesch-Nyhan Syndrome: Clinical Outcomes and Connectivity Analysis.

BACKGROUND: Lesch-Nyhan syndrome (LNS) is a rare genetic disorder characterized by a deficiency of hypoxanthine-guanine phosphoribosyltransferase enzyme. It manifests during infancy with compulsive self-mutilation behavior associated with disabling generalized dystonia and dyskinesia. Clinical management of these patients poses an enormous challenge for medical teams and carers. OBJECTIVES: We report our experience with bilateral deep brain stimulation (DBS) of the globus pallidus internus (GPi) in the management of this complex disorder. MATERIALS AND METHODS: Preoperative and postoperative functional assessment data prospectively collected by a multidisciplinary pediatric complex motor disorders team, including imaging, neuropsychology, and neurophysiology evaluations were analyzed with regards to motor and behavioral control, goal achievement, and patient and caregivers' expectations. RESULTS: Four male patients (mean age 13 years) underwent DBS implantation between 2011 and 2018. Three patients received double bilateral DBS electrodes within the posteroventral GPi and the anteromedial GPi, whereas one patient had bilateral electrodes placed in the posteroventral GPi only. Median follow-up was 47.5 months (range 22-98 months). Functional improvement was observed in all patients and discussed in relation to previous reports. Analysis of structural connectivity revealed significant correlation between the involvement of specific cortical regions and clinical outcome. CONCLUSION: Combined bilateral stimulation of the anteromedial and posteroventral GPi may be considered as an option for managing refractory dystonia and self-harm behavior in LNS patients. A multidisciplinary team-based approach is essential for patient selection and management, to support children and families, to achieve functional improvement and alleviate the overall disease burden for patients and caregivers.

DRAQ7 as an Alternative to MTT Assay for Measuring Viability of Glioma Cells Treated With Polyphenols.

BACKGROUND/AIM: The tetrazolium-based MTT cytotoxicity assay is well established for screening putative anti-cancer agents. However, it has limitations including lack of reproducibility with glioma cells treated with polyphenols. The aim of this study was to evaluate whether a flow cytometric assay with the anthraquinone, DRAQ7, was a better alternative than the colorimetric MTT assay for measuring cell viability. MATERIALS AND METHODS: Two glioma cell lines (IPSB-18, U373) and 1 pancreatic cancer cell line (AsPC-1) were treated with 4 polyphenols, namely red grape seed extract, red clover extract, anthocyanin-rich extract and curcumin. Cell viability was assessed using MTT assay and DRAQ7 staining. RESULTS: Limitations of MTT assay included lack of sensitivity and interference with the structure and absorbance spectra of polyphenols. Also, DMSO was toxic to glioma cells. Microscopic observations of cells treated with polyphenols confirmed the range of IC50 values evaluated by DRAQ7, but not by the MTT assay. CONCLUSION: DRAQ7 is a better alternative than MTT for measuring viability of glioma cells treated with brightly coloured polyphenols.

Subacute neocortical stimulation (SNCS) and its effects on epileptic activity in adults and children diagnosed with focal cortical dysplasia (FCD).

BACKGROUND: Chronic intracranial electrical stimulation is now widely used as treatment for drug resistant epilepsy. Subacute neocortical stimulation (SNCS) can also be performed during EEG recordings with intracranial electrodes (iEEG), but its diagnostic value remains largely unknown. METHODS: We assessed the effects of SNCS on the frequency of seizures and epileptiform discharges (EDs) during 290 h of iEEG- from 12 patients (6 adults, 6 children) with epilepsy secondary to focal cortical dysplasia (FCD). RESULTS: In 9/12 patients, SNCS periods showed decreased seizure-frequency (Median -73 %, p = 0.0093). At baseline, incidence of EDs were correlated with seizure-frequency (Spearman r = 0.59). However, this correlation disappeared during SNCS and a significant change in the incidence of EDs was observed. In addition, there was a trend towards greater reduction in seizure-frequency during SNCS in patients who underwent surgery. CONCLUSION: In summary, SNCS can reduce seizure-frequency and changes ED-frequency. The variability in ED changes may be explained by different effects of SNCS depending on electrode location. The magnitude of seizure reduction during SNCS suggests that this technique could contribute to preoperative assessment in epilepsy surgery.

Deep brain stimulation reduces pain in children with dystonia, including in dyskinetic cerebral palsy.

AIM: To establish the prevalence of dystonic pain in children and their response to deep brain stimulation (DBS). METHOD: Dystonic pain was assessed in a cohort of 140 children, 71 males and 69 females, median age 11 years 11 months (range 3y-19y 1mo), undergoing DBS in our centre over a period of 10 years. The cohort was divided into aetiological dystonia groups: 1a, inherited; 1b, heredodegenerative; 2, acquired; and 3, idiopathic. Motor responses were measured with the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). RESULTS: Dystonic pain was identified in 63 (45%) patients, 38% of whom had a diagnosis of cerebral palsy (CP). Dystonic pain improved in 90% of children and in all aetiological subgroups 1 year after DBS, while the BFMDRS motor score improved in 70%. Statistically significant improvement (p<0.01) was noted for the whole cohort on the Numerical Pain Rating Scale (n=27), Paediatric Pain Profile (n=17), and Caregivers Priorities and Child Health Index of Life with Disabilities questionnaire (n=48). There was reduction of pain severity, frequency, and analgesia requirement. Findings were similar for the whole cohort and aetiological subgroups other than the inherited heredodegenerative group where the improvement did not reach statistical significance. INTERPRETATION: Dystonic pain is frequent in children with dystonia, including those with CP, who undergo DBS; this can be an important, realizable goal of surgery irrespective of aetiology. We encourage the use of multimodal approach in pain research to reduce the risk of bias.

The subcortical belly of sleep: New possibilities in neuromodulation of basal ganglia?

Early studies posited a relationship between sleep and the basal ganglia, but this relationship has received little attention recently. It is timely to revisit this relationship, given new insights into the functional anatomy of the basal ganglia and the physiology of sleep, which has been made possible by modern techniques such as chemogenetic and optogenetic mapping of neural circuits in rodents and intracranial recording, functional imaging, and a better understanding of human sleep disorders. We discuss the functional anatomy of the basal ganglia, and review evidence implicating their role in sleep. Whilst these studies are in their infancy, we suggest that the basal ganglia may play an integral role in the sleep-wake cycle, specifically by contributing to a thalamo-cortical-basal ganglia oscillatory network in slow-wave sleep which facilitates neural plasticity, and an active state during REM sleep which enables the enactment of cognitive and emotional networks. A better understanding of sleep mechanisms may pave the way for more effective neuromodulation strategies for sleep and basal ganglia disorders.

Centromedian thalamic nuclei deep brain stimulation and Anakinra treatment for FIRES - Two different outcomes.

Febrile infection-related epilepsy syndrome (FIRES) is a severe epilepsy disorder that affects previously healthy children. It carries high likelihood of unfavourable outcome and putative aetiology relates to an auto-inflammatory process. Standard antiepileptic drug therapies including intravenous anaesthetic agents are largely ineffective in controlling status epilepticus in FIRES. Deep brain stimulation of the centromedian thalamic nuclei (CMN-DBS) has been previously used in refractory status epilepticus in only a few cases. The use of Anakinra (a recombinant version of the human interleukin-1 receptor antagonist) has been reported in one case with FIRES with good outcome. Here we describe two male paediatric patients with FIRES unresponsive to multiple anti-epileptic drugs, first-line immune modulation, ketogenic diet and cannabidiol. They both received Anakinra and underwent CMN-DBS. The primary aim for CMN-DBS therapy was to reduce generalized seizures. CMN-DBS abolished generalized seizures in both cases and Anakinra had a positive effect in one. This patient had a favourable outcome whereas the other did not. These are the first reported cases of FIRES where CMN-DBS has been used.