From symptom onset to ED departure: understanding the acute care chain for patients with undifferentiated complaints: a prospective observational study.

BACKGROUND: For most acute conditions, the phase prior to emergency department (ED) arrival is largely unexplored. However, this prehospital phase has proven an important part of the acute care chain (ACC) for specific time-sensitive conditions, such as stroke and myocardial infarction. For patients with undifferentiated complaints, exploration of the prehospital phase of the ACC may also offer a window of opportunity for improvement of care. This study aims to explore the ACC of ED patients with undifferentiated complaints, with specific emphasis on time in ACC and patient experience. METHODS: This Dutch prospective observational study, included all adult (≥ 18 years) ED patients with undifferentiated complaints over a 4-week period. We investigated the patients' journey through the ACC, focusing on time in ACC and patient experience. Additionally, a multivariable linear regression analysis was employed to identify factors independently associated with time in ACC. RESULTS: Among the 286 ED patients with undifferentiated complaints, the median symptom duration prior to ED visit was 6 days (IQR 2-10), during which 58.6% of patients had contact with a healthcare provider before referral. General Practitioners (GPs) referred 80.4% of the patients, with the predominant patient journey (51.7%) involving GP referral followed by self-transportation to the ED. The median time in ACC was 5.5 (IQR 4.0-8.4) hours of which 40% was spent before the ED visit. GP referral and referral to pulmonology were associated with a longer time in ACC, while referral during evenings was associated with a shorter time in ACC. Patients scored both quality and duration of the provided care an 8/10. CONCLUSION: Dutch ED patients with undifferentiated complaints consulted a healthcare provider in over half of the cases before their ED visit. The median time in ACC is 5.5 h of which 40% is spent in the prehospital phase. Those referred by a GP and to pulmonology had a longer, and those in the evening a shorter time in ACC. The acute care journey starts hours before patients arrive at the ED and 6 days of complaints precede this journey. This timeframe could serve as a window of opportunity to optimise care.

Progressive multifocal leukoencephalopathy secondary to idiopathic CD4 lymphocytopenia treated with pembrolizumab.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease due to a lytic infection of oligodendrocytes caused by John Cunningham polyoma virus (JCV) infection. Idiopathic CD4+ T-cell lymphocytopenia (ICL) is a very rare cause of PML. METHODS: We present an individual with PML secondary to ICL treated with 3 doses of pembrolizumab, a Programmed-Death-1 Immune Checkpoint Inhibitor following with complete resolution of symptoms and conduct a review of the literature. CONCLUSION: This report illustrates the objective clinical and radiological improvement in a patient with PML due to ICL and suggests further study of immune checkpoint inhibitors as potential treatment for patients with PML.

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.

Context effects, skin conductance responses and personality traits - Influencing variables on risk-taking within a modified version of the balloon analog risk task.

When individuals take risks, they must weigh potential costs and benefits associated with a decision. Differences in risk-taking appear to be influenced by contextual, and inter-individual factors. However, it is still ambiguous to what extent these characteristics jointly influence risk-taking. We investigated how risk-taking varies as function of context effects, incentives, skin conductance responses (SCR), and personality traits such as impulsivity and sensitivity to reward and punishment. Sixty-eight healthy participants conducted a modified version of the Balloon Analogue Risk Task (BART) composed of a gain-framed (G-BART) and loss-framed (L-BART) context with each a low and a high outcome magnitude condition. While the goal in G-BART was to maximize gains, the goal in L-BART was to minimize losses. In both versions, participants can potentially accumulate the same amounts. We conducted trial-by-trial mixed model analyses to account for within- and between-participant effects. Participants showed greater risk-taking when playing L-BART than G-BART; more risk-taking was observed in the high compared to the low outcome magnitude condition. Furthermore, higher SCR were associated with less risk-taking. Lower impulsivity was related to a greater difference in risk-taking in both contexts, with greater risk-taking in L-BART. Likewise, sensitivity to reward was associated with a greater difference in risk-taking in both contexts, with greater risk-taking in G-BART. Finally, greater sensitivity to punishment was related to risk-taking among participants describing themselves as sensitive to rewards. Results support a multidimensional state-trait model of risk-taking suggesting that risk-taking is favored by loss-aversion along with incentives, psychophysiological arousal, and personality traits.

Two-center experience of cannabidiol use in adults with Dravet syndrome.

We describe real-world experience with cannabidiol (CBD) in adults with Dravet Syndrome (DS) via GW Pharma early access programme at two UK neurology centres. Adults with genetically-confirmed DS had CBD added to existing therapy, titrated up to 20 mg/kg, as tolerated. The primary outcome measure was percentage reduction in convulsive seizures. Secondary outcome measures included changes in myoclonic seizures, and in cognition and quality of life as assessed by the Caregiver Global Impression of Change (CGIC), and incidence of adverse events (AEs). 18 adults (7 female; median age 27.5 years; range 20-51) were included. Median follow-up was 176 days. In one, another antiseizure drug, clobazam, was introduced during the programme. 3/17 (17.6%) had >30% reduction in convulsive seizures (range: 87.5-100%). AEs occurred in all, the most common being transaminitis (52.9%). Behavioural AEs led to discontinuation in 3/18 (16.7%), including a seizure-free responder. In 7/18, CBD was stopped due to lack of effect. 8/18 continue on treatment. Improvements in CGIC were reported in 41.2% and 47.1% by physicians and families, respectively. 17.6% achieved sufficient reduction in convulsive seizure frequency to qualify for NHS funding. AEs led to withdrawal in only 16.7%. Close monitoring and dose adjustments of other antiseizure drugs were necessary.

New-onset refractory status epilepticus (NORSE).

New-onset refractory status epilepticus and its subcategory febrile infection-related epilepsy syndrome are rare devastating clinical presentations in those without pre-existing relevant history, often in schoolchildren or young adults, without a clear cause on initial investigations. A cause is later identified in up to half of adults, but in many fewer children. Patients often require protracted intensive care and are at significant risk of dying. Functional disability is common and subsequent chronic epilepsy is the norm, but some people do have good outcomes, even after prolonged status epilepticus. Patients need prompt investigations and treatment. Anaesthetic and antiseizure medications are supplemented by other treatment modalities, including the ketogenic diet. Despite limited evidence, it is appropriate to try to modify the presumed underlying pathogenesis with immune modulation early, with a more recent focus on using interleukin inhibitors. Optimising management will require concerted multicentre international efforts.

Non-convulsive status epilepticus: COVID-19 or clozapine induced?

We present a case of non-convulsive status epilepticus in a 57-year-old woman with a schizoaffective disorder, without an antecedent seizure history, with two possible aetiologies including SARS-CoV-2 infection and clozapine uptitration. We discuss the presentation, investigations, differential diagnosis and management. In particular, we focus on the electroencephalogram (EEG) findings seen in this case and the electroclinical response to antiepileptic medication. We review the literature and discuss the relevance of this case to the SARS-CoV-2 global pandemic. We emphasise the importance of considering possible neurological manifestations of SARS-CoV-2 infection and highlight seizure disorder as one of the possible presentations. In addition, we discuss the possible effects of clozapine on the electroclinical presentation by way of possible seizure induction as well as discuss the possible EEG changes and we highlight that this needs to be kept in mind especially during rapid titration.

Visual and semiautomated evaluation of epileptogenicity in focal cortical dysplasias - An intracranial EEG study.

INTRODUCTION: The aim of the study was the evaluation of the added value of depth to subdural electrodes in delineating epileptogenicity of focal cortical dysplasias (FCDs) and to test the Epileptogenicity Index (EI) in this setting. MATERIAL AND METHODS: Fifteen patients with FCD underwent iEEG with subdural and depth electrodes. Visual/EI analysis was performed in up to three habitual seizures per patient. RESULTS: Visual analysis: Grid onset seizures (n=10) started in electrodes overlying the lesion in 7 and remote from it in 3 cases. Depth onset seizures (n=7) affected only intralesional contacts in 4, intra- and extralesional in 2, and exclusively extralesional in 1 patient. Seizures started in depth and grid contacts simultaneously in 2 cases. EI analysis: The EI completely confirmed visual localization of seizure onset in 8 cases and depicted ictal onset-time accurately in 13. Beta/gamma ictal patterns were most reliably captured. Impact on surgical decision: Resection outline differed from MRI lesion in 7 patients based on grid and in three based on depth electrode information. DISCUSSION: In FCD, seizures can be generated within gyral/deep tissue appearing normal on imaging. CONCLUSION: Investigating FCD with subdural and depth electrodes is efficient to outline the seizure onset zone. The EI is a helpful additional tool to quantify epileptogenicity. Specific ictal patterns are prerequisite for reliable results.

Lentiviral expression of GAD67 and CCK promoter-driven opsins to target interneurons in vitro and in vivo.

BACKGROUND: The ability to manipulate the activity of interneurons with optogenetic tools offers the possibility of interfering with diseases caused by altered neuronal inhibition and synchrony, including epilepsy and schizophrenia. To develop vectors for therapeutic approaches, targeting optogenetic constructs to interneurons is therefore a key requirement. We investigated whether the interneuron-specific promoters glutamic acid decarboxylase (GAD)67 and cholecystokinin (CCK) allowed targeted lentiviral delivery of opsins to interneurons as a whole, or specifically CCK+ interneurons. METHODS: We generated lentiviral (LV) plasmids encoding channelrhodopsin (ChR2) and halorhodopsin (NpHR) tagged with fluorophores and driven by GAD67 or CCK promoters. Adeno-associated virus (AAV) and LV vectors carrying opsins driven by pyramidal cell promoters were used as controls. We transduced neuronal cultures and rodent brain in vivo, immunostained specimens 6-8 weeks after in vivo injection and 7-14 days after in vitro transduction, and evaluated volume and specificity of expression by confocal microscopy. RESULTS: In vitro, 90% (19/21) of LV-CCK-NpHR2.0-EYFP expressing neurons were CCK+. In vivo, LV-GAD67-ChR2-mCherry was expressed in 2.6% (5/193), LV-GAD67-NpHR2.0-EYFP in approximately 15% (43/279) and LV-CCK-NpHR2.0-EYFP in 47% (9/19) of hippocampal GABA+ interneurons. GAD67 vectors expressed in larger volumes than CCK-driven constructs. AAV vector controls achieved the largest expression volumes. CONCLUSIONS: LV-CCK-NpHR2.0-EYFP may be useful for targeting CCK+ interneurons in culture. GAD67/CCK-driven lentiviral constructs are expressed in vivo, although expression is not specific for interneurons. Overall, expression levels are low compared to opsins driven by pyramidal cell promoters. A better understanding of GAD67 and CCK promoter structure or alternative techniques is required to reliably target opsins to interneurons using viral vectors.

WONOEP appraisal: optogenetic tools to suppress seizures and explore the mechanisms of epileptogenesis.

Optogenetics is a novel technology that combines optics and genetics by optical control of microbial opsins, targeted to living cell membranes. The versatility and the electrophysiologic characteristics of the light-sensitive ion-channels channelrhodopsin-2 (ChR2), halorhodopsin (NpHR), and the light-sensitive proton pump archaerhodopsin-3 (Arch) make these optogenetic tools potent candidates in controlling neuronal firing in models of epilepsy and in providing insights into the physiology and pathology of neuronal network organization and synchronization. Opsins allow selective activation of excitatory neurons and inhibitory interneurons, or subclasses of interneurons, to study their activity patterns in distinct brain-states in vivo and to dissect their role in generation of synchrony and seizures. The influence of gliotransmission on epileptic network function is another topic of great interest that can be further explored by using light-activated Gq protein-coupled opsins for selective activation of astrocytes. The ever-growing optogenetic toolbox can also be combined with emerging techniques that have greatly expanded our ability to record specific subtypes of cortical and hippocampal neurons in awake behaving animals such as juxtacellular recording and two-photon guided whole-cell recording, to identify the specific subtypes of neurons that are altered in epileptic networks. Finally, optogenetic tools allow rapid and reversible suppression of epileptic electroencephalography (EEG) activity upon photoactivation. This review outlines the most recent advances achieved with optogenetic techniques in the field of epilepsy by summarizing the presentations contributed to the 13th ILAE WONOEP meeting held in the Laurentian Mountains, Quebec, in June 2013.

Characterization of motor units in behaving adult mice shows a wide primary range.

The mouse is essential for genetic studies of motor function in both normal and pathological states. Thus it is important to consider whether the structure of motor output from the mouse is in fact analogous to that recorded in other animals. There is a striking difference in the basic electrical properties of mouse motoneurons compared with those in rats, cats, and humans. The firing evoked by injected currents produces a unique frequency-current (F-I) function that emphasizes recruitment of motor units at their maximum force. These F-I functions, however, were measured in anesthetized preparations that lacked two key components of normal synaptic input: high levels of synaptic noise and neuromodulatory inputs. Recent studies suggest that the alterations in the F-I function due to these two components are essential for recreating firing behavior of motor units in human subjects. In this study we provide the first data on firing patterns of motor units in the awake mouse, focusing on steady output in quiet stance. The resulting firing patterns did not match the predictions from the mouse F-I behaviors but instead revealed rate modulation across a remarkably wide range (10-60 Hz). The low end of the firing range may be due to changes in the F-I relation induced by synaptic noise and neuromodulatory inputs. The high end of the range may indicate that, unlike other species, quiet standing in the mouse involves recruitment of relatively fast-twitch motor units.

Clinical reasoning: rapidly progressive quadriparesis in a forgetful patient.

A 50-year-old right-handed retired family business manager developed progressive left-sided weakness over 5 days after a mechanical fall. She remembered catching her foot on the carpet and falling down a flight of stairs, followed by severe neck pain over C4-C5 and inability to get up for nearly an hour. Over the subsequent month her symptoms progressed and she presented to hospital with an asymmetric spastic paraparesis, loss of pinprick sensation in her arms and legs, loss of vibration sense to both hips, and double incontinence.

Collaboration of a model osteoporosis prevention and management program in a faith community.

This article describes the collaborative efforts of a parish nurse, family nurse practitioner, and a registered dietitian in a faith-based setting to address the women's health issue of osteoporosis. A model for education and treatment including lifestyle changes, nutrition, and pharmacological therapies is discussed. The whole person perspective of prevention and management for women with this chronic disease is explored. Implications for practice and education for women across the life span are described.

A primer of ethical issues involving opioid therapy for chronic nonmalignant pain in a multidisciplinary setting.

OBJECTIVE: This forum presents a clinical vignette of orofacial pain and expounds on ethical issues related to opioid therapy in the context of multidisciplinary treatment. The purpose of this forum is to assist health care providers from different disciplines in identifying ethical issues and conflicts regarding opioid therapy encountered in multidisciplinary clinical pain practices. DESIGN: We use the case vignette and opioid therapy as a backdrop for a discussion of 1) an overview of ethics terminology; 2) a presentation of key ethics principles; 3) our conceptualization of ethical obligations of patients regarding opioid therapy; and 4) the process of developing an appropriate treatment plan within the context of the discussed ethical principles.

Neurocognitive measures of prefrontal cortical dysfunction in schizophrenia.

Frontal lobe dysfunction in individuals with schizophrenia has frequently been detected using both neuroimaging and neuropsychological testing. Results from previous studies vary in the findings of regional specificity vs. generalized frontal cortical dysfunction. We sought to examine potential regional differences in frontal cortical functioning among patients with schizophrenia vs. a comparison group using two different neurocognitive tasks: the Gambling Task (GT) and the Wisconsin Card Sorting Test (WCST). In general, the GT is thought to reflect function of the ventromedial prefrontal cortex (VMPFC), while the WCST reflects function of the dorsolateral prefrontal cortex (DLPFC). Twenty individuals with schizophrenia or schizoaffective disorder and 15 nonpsychiatrically ill comparison subjects underwent an assessment battery consisting of the GT, WCST, and positive and negative symptom ratings. Patients with schizophrenia performed worse on the GT with respect to total monetary gain (p=0.05) and total monetary loss (p<0.05). They also preferred disadvantaged vs. advantaged cards (p<0.04). Surprisingly, WCST performance was poor in both groups and was not significantly different between groups. These findings are at some variance with those in the previously reported literature, but nonetheless support the idea that prefrontal cortical areas mediating different cognitive tasks may be distinguished by specific neurocognitive assessments.

Ontogeny of ionotropic glutamate receptor subunit expression in the rat hippocampus.

The ionotropic glutamate receptors play key roles in multiple developmental mechanisms, including regulation of neuronal migration and differentiation, and synaptic organization. In this study, we investigated the developmental expression of these glutamate receptors in the postnatal rat hippocampus. We examined the transcripts encoding the subunits composing the N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and kainate (KA) subtypes of glutamate receptors by in situ hybridization at multiple time points from postnatal day (PND) 1 to PND 35. In the case of the AMPA receptor, gluR1 expression did not change over this time period, while gluR2, gluR3, and gluR4 did. These three subunits each underwent a transient period of increased expression at either PND 7 or PND 18. All five of the kainate receptor subunits changed during this time, all starting at relatively high levels of expression that declined by PND 35. Similar to most of the AMPA subunits, all of the kainate subunits had transient periods of significantly increased expression. The NMDA receptors all changed during over time as well, and each had a period of increased expression. The periods of transiently increased expression of all of these subunits coincide with known periods of plasticity and other critical times in development. These results suggest the different glutamate receptor subtypes may be critical at specific times during postnatal brain development.