Sodium selenate as a disease-modifying treatment for mild–moderate Alzheimer’s disease: an open-label extension study

IntroductionSodium selenate is a potential disease-modifying treatment for Alzheimer’s disease (AD) which reduces hyperphosphorylated tau through activation of the protein phosphatase 2A enzyme. We have shown sodium selenate to be safe and well tolerated in a 24-week, phase 2a double-blind placebo-controlled randomised controlled trial (RCT), also reporting sodium selenate reduced neurodegeneration on diffusion-weighted MRI. This study assessed the safety and tolerability of chronic sodium selenate treatment (up to 23 months) in patients with AD who had been enrolled in the RCT. Cognitive measures served as secondary outcomes of potential disease-modification.MethodsAn open-label extension study of sodium selenate (10 mg three times a day) in patients with AD who had completed the previous RCT. Twenty-eight patients were enrolled. Patients were regularly monitored for safety, adverse events (AEs) and protocol compliance. Cognitive tests were administered for measures of disease progression.ResultsSixteen patients were discontinued by the sponsor, and 12 discontinued for other reasons. Treatment duration ranged from 6 to 23 months. The majority of AEs were mild (83%), and 33% were treatment-related. Common treatment-related AEs were alopecia (21%) and nail disorder (32%), which both resolved either prior to or following cessation of treatment. Two serious AEs occurred, which were not treatment-related. Alzheimer’s Disease Assessment Scale—Cognitive Subscale 11 score increased 1.8 points over 12 months.DiscussionChronic sodium selenate treatment is safe and well tolerated in patients with AD. Cognitive measures suggest a slowing of disease progression though this could not be confirmed as the study was not controlled. Further research into sodium selenate as a treatment for AD is warranted.

Computerised analysis of writing and drawing by essential tremor phenotype

We investigated whether computerised analysis of writing and drawing could discriminate essential tremor (ET) phenotypes according to the 2018 Consensus Statement on the Classification of Tremors. The Consensus scheme emphasises soft additional findings, mainly motor, that do not suffice to diagnose another tremor syndrome. Ten men and nine women were classified by blinded assessors according to Consensus Axis 1 definitions of ET and ET plus. Blinded scoring of tremor severity and alternating limb movement was also conducted. Twenty healthy participants acted as controls. Four writing and three drawing tasks were performed on a Wacom Intuos Pro Large digital tablet with a pressure-sensor mounted ink pen. Sixty-seven computerised measurements were obtained, comprising static (dimensional and temporal), kinematic and pen pressure features. The mean age of ET participants was 67.2±13.0 years and mean tremor duration was 21.7±19.0 years. Six were classified as ET, five had one plus feature and eight had two plus features. The computerised analysis could predict the presence and number of ET plus features. Measures of acceleration and variation of pen pressure performed strongly to separate ET phenotypes (p<0.05). Plus features were associated with higher scores on the Fahn-Tolosa-Marin Tremor Rating Scale (p=0.001) and it appeared that ET groups were mainly being separated according to severity of tremor and by compensatory manoeuvres used by participants with more severe tremor. There were, in addition, a small number of negative kinematic correlations suggesting some slowness with ET plus. Abnormal repetitive limb movement was also correlated with tremor severity (R=0.57) by clinical grading. Critics of the Consensus Statement have drawn attention to weaknesses of the ET plus concept in relation to duration and severity of ET. This classification of ET may be too biased towards tremor severity to assist in distinguishing underlying biological differences by clinical measurement.

DelIrium VULnerability in GEriatrics (DIVULGE) study: a protocol for a prospective observational study of electroencephalogram associations with incident postoperative delirium

IntroductionDelirium is a neurocognitive disorder common in older adults in acute care settings. Those who develop delirium are at an increased risk of dementia, cognitive decline and death. Electroencephalography (EEG) during delirium in older adults is characterised by slowing and reduced functional connectivity, but markers of vulnerability are poorly described. We aim to identify EEG spectral power and event-related potential (ERP) markers of incident delirium in older adults to understand neural mechanisms of delirium vulnerability. Characterising delirium vulnerability will provide substantial theoretical advances and outcomes have the potential to be translated into delirium risk assessment tools.Methods and analysisWe will record EEG in 90 participants over 65 years of age prior to elective coronary artery bypass grafting (CABG) or transcatheter aortic valve implantation (TAVI). We will record 4-minutes of resting state (eyes open and eyes closed) and a 5-minute frequency auditory oddball paradigm. Outcome measures will include frequency band power, 1/f offset and slope, and ERP amplitude measures. Participants will undergo cognitive and EEG testing before their elective procedures and daily postoperative delirium assessments. Group allocation will be done retrospectively by linking preoperative EEG data according to postoperative delirium status (presence, severity, duration and subtype).Ethics and disseminationThis study is approved by the Human Research Ethics Committee of the Royal Adelaide Hospital, Central Adelaide Local Health Network and the University of South Australia Human Ethics Committee. Findings will be disseminated through peer-reviewed journal articles and presentations at national and international conferences.Trial registration numberACTRN12618001114235 and ACTRN12618000799257.

Vagus nerve stimulation therapy in people with drug-resistant epilepsy (CORE-VNS): rationale and design of a real-world post-market comprehensive outcomes registry

IntroductionThe Vagus Nerve Stimulation Therapy System (VNS Therapy) is an adjunctive neuromodulatory therapy that can be efficacious in reducing the frequency and severity of seizures in people with drug-resistant epilepsy (DRE). CORE-VNS aims to examine the long-term safety and clinical outcomes of VNS in people with DRE.Methods and analysisThe CORE-VNS study is an international, multicentre, prospective, observational, all-comers, post-market registry. People with DRE receiving VNS Therapy for the first time as well as people being reimplanted with VNS Therapy are eligible. Participants have a baseline visit (prior to device implant). They will be followed for a minimum of 36 months and a maximum of 60 months after implant. Analysis endpoints include seizure frequency (average number of events per month), seizure severity (individual-rated categorical outcome including very mild, mild, moderate, severe or very severe) as well as non-seizure outcomes such as adverse events, use of antiseizure medications, use of other non-pharmacological therapies, quality of life, validated measures of quality of sleep (Pittsburgh Sleep Quality Index or Children’s Sleep Habit Questionnaire) and healthcare resource utilisation. While the CORE-VNS registry was not expressly designed to test hypotheses, subgroup analyses and exploratory analysis that require hypothesis testing will be conducted across propensity score matched treatment groups, where possible based on sampling.Ethics and disseminationThe CORE-VNS registry has already enrolled 823 participants from 61 centres across 15 countries. Once complete, CORE-VNS will represent one of the largest real-world clinical data sets to allow a more comprehensive understanding of the management of DRE with adjunctive VNS. Manuscripts derived from this database will shed important new light on the characteristics of people receiving VNS Therapy; the practical use of VNS across different countries, and factors influencing long-term response.Trail registration numberNCT03529045.

Driving restrictions following deep brain stimulation surgery

BackgroundThere are currently no Australian guidelines to assist clinicians performing deep brain stimulation (DBS) procedures in setting postoperative driving restrictions.PurposeWe aimed to provide recommendations for post-DBS driving restrictions to guide practice in Australia.MethodsA review of current Australian and international driving guidelines, literature regarding the adverse effects of DBS and literature regarding the long-term effect of neurostimulation on driving was conducted using Elton B Stephens Company discovery service-linked databases. Australian neurologists and neurosurgeons who perform DBS were surveyed to gain insight into existing practice.ResultsNo guidance on driving restrictions following DBS surgery was found, either in existing driving guidelines or in the literature. There was a wide difference seen in the rates of reported adverse effects from DBS surgery. The most serious adverse events (haemorrhage, seizure and neurological dysfunction) were uncommon. Longer term, there does not appear to be any adverse effect of DBS on driving ability. Survey of Australian practitioners revealed a universal acceptance of the need for and use of driving restrictions after DBS but significant heterogeneity in how return to driving is managed.ConclusionWe propose a 6-week driving restriction for private licences and 6-month driving restriction for commercial licences in uncomplicated DBS. We also highlight some of the potential pitfalls and pearls to assist clinicians to modify these recommendations where needed. Ultimately, we hope this will stimulate further examination of this issue in research and by regulatory bodies to provide more robust direction for practitioners performing DBS implantation.

Single-centre study surveying neurology trainees’ and faculty’s perceptions of the impact of the COVID-19 pandemic on residents’ medical education

ObjectiveTo assess perceptions of our neurology residents and faculty regarding training experience and medical education during the early COVID-19 pandemic.MethodsWe distributed two online, voluntary and anonymous surveys to trainees and teaching faculty of our Neurology Department at Henry Ford Hospital. Surveys inquired about trainees’ stress, well-being, clinical experience and satisfaction with medical education and available support resources during the first wave of the COVID-19 pandemic in Michigan (mid-March to June 2020).ResultsA total of 17/31 trainees and 25/42 faculty responded to the surveys. Eight (47%) trainees reported high stress levels. Nine (57%) were redeployed to cover COVID-19 units. Compared with non-redeployed trainees, redeployed residents reported augmented medical knowledge (89% vs 38%, p=0.05). There was no difference in the two groups regarding overall satisfaction with residency experience, stress levels and didactics attendance. Twenty-one (84%) faculty felt that the redeployment interfered with trainees education but was appropriate, while 10 (59%) trainees described a positive experience overall. Both trainees and faculty believed the pandemic positively impacted trainees’ experience by increasing maturity level, teamwork, empathy, and medical knowledge, while both agreed that increased stress and anxiety levels were negative outcomes of the pandemic. Twelve (70%) trainees and 13 (52%) faculty were interested in pursuing more virtual didactics in the future.ConclusionOur findings provide an objective assessment of residents' experience during the COVID-19 pandemic and can guide teaching programmes in their medical education response in the face of future global crises.

Experiences of remote consulting for patients and neurologists during the COVID-19 pandemic in Scotland

BackgroundRemote consulting is an emerging model in managing chronic neurological conditions and has been widely implemented during the COVID-19 pandemic. The objective of this national survey was to investigate the initial experiences of remote consulting for neurologists and patients with established neurological conditions under follow-up during the first COVID-19 phase.MethodsIn collaboration with the Scottish Association of Neurological Sciences and the Neurological Alliance of Scotland, we conducted a web-based survey of neurologists and patients between October and November 2020.FindingsData was available for 62 neurologists and 201 patients. The consensus among neurologists was that remote consulting is a satisfactory way of delivering healthcare in selected groups of patients. For practical and technical reasons, there was preference for phone over video consultations (phone 63% vs video 33%, p=0.003). The prevailing opinion among clinicians was that considerable training interventions for remote consultation skills are required (‘yes’ 63% vs ‘no’ 37%, p=0.009) to improve clinician consultation skills and successfully embed this new model of care.Most patients perceived remote consultations as safe, effective and convenient, with 89% of patients being satisfied with their remote consultation experience. Although traditional face-to-face consultations were the favoured way of interaction for 62% of patients, a significant proportion preferred that some of their future consultations be remote.InterpretationAlthough not a replacement for face-to-face consultations, this survey illustrates that remote consulting can be an acceptable adjunct to traditional face-to-face consultations for doctors and patients. More research is required to identify overall safety and applicability.

Antibodies to neurofilament light as potential biomarkers in multiple sclerosis

Background and objectiveThe concentration of neurofilament light (NfL) protein in cerebrospinal fluid (CSF) and blood is widely considered as a quantitative measure of neuro-axonal injury. Immune reactivity to NfL released into extracellular fluids induces specific autoantibody response. We investigated the levels and avidity of antibodies to NfL in patients with multiple sclerosis (MS) treated with disease-modifying therapies (DMTs) and their correlation with disease worsening and NfL protein concentration.MethodsWe conducted a prospective longitudinal study in 246 patients with MS (125 DMT-treated and 121 untreated at baseline). Serum levels of NfL antibodies, antibody avidity and immune complexes were determined by ELISA. NfL protein was measured using the Simoa platform. Clinical variables were tested for their association with the measured parameters in multivariate generalised estimating equation models.ResultsMultivariate analysis showed that levels of NfL antibodies were higher in progressive MS compared with clinically isolated syndrome (CIS)/relapsing remitting multiple sclerosis (RRMS) (p=0.010). Anti-NfL levels drop with increasing disability score (Expanded Disability Status Scale (EDSS)) (p=0.002), although conversely, were significantly elevated in CIS/RRMS after a recent EDSS increase (p=0.012). Patients receiving DMTs showed decreased levels of anti-NfL (p=0.008), high-avidity antibodies (p=0.017) and immune-complexes compared with untreated CIS/RRMS. Patients with MS switching to natalizumab showed lower levels of anti-NfL but higher immune complexes compared with healthy controls (p=0.0071). A weak association was observed between the levels of NfL protein and NfL antibodies.ConclusionsThese results support the potential usefulness of quantifying antibody response to NfL as potential markers of progression and treatment response in MS and need to be considered when interpreting peripheral blood NfL levels.

Association between systolic blood pressure course and outcomes after stroke thrombectomy

BackgroundSystolic blood pressure (SBP) after endovascular thrombectomy (EVT) for large artery occlusive stroke is dynamic, requiring adaptable early prediction tools for improving outcomes. We investigated if post-EVT SBP course was associated with outcomes.MethodsEVT-treated patients who had a stroke at Karolinska University Hospital, Stockholm, Sweden, were included in the study during 12 February 2018–11 February 2020. SBP was recorded during the first 24 hours after EVT. Primary outcome was functional independence defined by a Modified Rankin Scale score of 0–2 at 3 months. Secondary outcomes were death by 3 months, symptomatic intracranial haemorrhage and any intracranial haemorrhage. Patients with favourable outcomes were used as a reference SBP course in mixed linear effects models and compared with SBP courses of patients with unfavourable outcomes using the empirical best linear unbiased predictor, measuring deviations from the reference SBP course using the random effects. We tested model predictive stability for SBP measurements of only 18, 12 or 6 hours after EVT.Results374 patients were registered, with mean age 71, median NIHSS score of 15, and 53.2% men. Deviating from a linear SBP course starting at 130 mm Hg and decreasing to 123 mm Hg at 24 hours after EVT was associated with lower chances of functional independence (adjusted OR 0.53, 95% CI 0.29 to 0.88, for reaching either 99 or 147 mm Hg at 24 hours after EVT). All SBP course models for the remaining outcomes did not show statistical significance. Functional independence models showed stable predictive values for all time periods.ConclusionDeviating from a linear SBP course was associated with lower chances of 3-month functional independence.

Migraine and tension-type headache among undergraduate medical, dental and pharmaceutical students of University of Aleppo: a cross-sectional study

IntroductionHeadache disorders are among the most common 10 causes of disability worldwide according to the global burden of disease survey 2010. Headache is also wildly common among universities students when compared with other populations. The purpose of this study is to assess headache prevalence among Aleppo University medical, dental and pharmaceutical undergraduate students.MethodsA questionnaire-based cross-sectional study was conducted among medical, dental and pharmaceutical students at Aleppo University, Syria. We determined the type of headache according to the International Classification of Headache Disorder-III. The total number of participants was 2068. A χ2 test was used to evaluate the association between the categorical outcomes. P<0.05 was considered significant.ResultsOut of 2068 participants, 1604 (77.6%) were medical students, 205 (9.9%) were dental students and 259 (12.5%) were pharmaceutical students. The effect on daily activities was higher in chronic tension headache (96.7%) and migraine without aura (94.6%) than migraine with aura (91.3) and episodic tension headache (85.1%). Out of 1191 who had a headache, only 188 (15.9%) had a medical consultation.ConclusionsThere was no a statistically significant difference in prevalence of tension headache and migraine according to faculties. There was a statistically significant difference in patients with migraine according to academic year, living with family and smoking. The effect on daily activities was higher in chronic tension-type headache and migraine without aura. There is a significant lack of medical consultation among students and most of them took over the counter analgesics depending on personal choice.