Increased Intrathecal B and Plasma Cells in Patients With Anti-IgLON5 Disease

Background and ObjectivesDespite detection of autoantibodies, anti-IgLON5 disease was historically considered a tau-associated neurodegenerative disease, with limited treatment options and detrimental consequences for the patients. Observations in increasing case numbers hint toward underlying inflammatory mechanisms that, early detection provided, open a valuable window of opportunity for therapeutic intervention. We aimed to further substantiate this view by studying the CSF of patients with anti-IgLON5.MethodsWe identified 11 patients with anti-IgLON5 from our database and compared clinical, MRI, and CSF findings with a cohort of 20 patients with progressive supranuclear palsy (PSP) (as a noninflammatory tauopathy) and 22 patients with functional neurologic disorder.ResultsPatients with anti-IgLON5 show inflammatory changes in routine CSF analysis, an increase in B-lymphocyte frequency, and the presence of plasma cells in comparison to the PSP-control group and functional neurologic disease controls. Patients with intrathecal plasma cells showed a clinical response to rituximab.DiscussionOur findings indicate the importance of inflammatory mechanisms, in particular in early and acute anti-IgLON5 cases, which may support the use of immune-suppressive treatments in these cases. The main limitation of the study is the small number of cases due to the rarity of the disease.

In-Hospital Cardiac Arrest: Patient Characteristics and Factors Influencing Survival and Neurologic Outcomes

Objective: We aimed to determine the characteristics of in-hospital cardiac arrest (IHCA) patients, as well as the factors influencing survival to discharge and good neurologic outcome.Methods: We examined patients who experienced IHCA from January 1, 2011, to December 31, 2013, in Soonchunhyang University Seoul Hospital. They were divided into a survival group and non-survival group. The patient characteristics, including age, sex, comorbid disease, arrest time, arrest location, witnessed arrest, monitoring, arrest cause, arrest rhythm, and cardiopulmonary resuscitation (CPR) duration, were compared between the groups. Moreover, we assessed the factors associated with survival to discharge and good neurologic outcomes by using multivariate logistic regression analysis.Results: In total, 453 patients of IHCA were observed. The comorbidities in the survival group included neurologic disease (P < 0.001), arrhythmia (P = 0.001), and myocardial infarction (P = 0.032), pneumonia (P = 0.016). Other characteristics included cardiac arrest at daytime (P = 0.032), cardiogenic arrest cause (P = 0.019), and CPR duration < 15 minutes (P < 0.001). The factors associated with survival to discharge included comorbid neurologic disease (odds ratio [OR], 2.191; P = 0.031), arrhythmia (OR, 3.027; P = 0.009), pneumonia (OR, 3.243; P = 0.002), and CPR duration < 15 minutes (OR, 9.638; P < 0.001). The factors influencing good neurologic outcomes included age < 65 years (OR, 3.158; P = 0.007), comorbid disease as arrhythmia (OR, 4.921; P = 0.001), pneumonia (OR, 4.551; P = 0.001), hypotension (OR, 4.264; P = 0.021), and CPR duration < 15 minutes (OR, 6.652; P = 0.001).Conclusion: The factors influencing survival to discharge and good neurologic outcomes among IHCA patients included comorbidities, arrest cause, and CPR duration.

Microglia do not restrict SARS-CoV-2 replication following infection of the central nervous system of K18-hACE2 transgenic mice

Unlike SARS-CoV-1 and MERS-CoV, infection with SARS-CoV-2, the viral pathogen responsible for COVID-19, is often associated with neurologic symptoms that range from mild to severe, yet increasing evidence argues the virus does not exhibit extensive neuroinvasive properties. We demonstrate SARS-CoV-2 can infect and replicate in human iPSC-derived neurons and that infection shows limited anti-viral and inflammatory responses but increased activation of EIF2 signaling following infection as determined by RNA sequencing. Intranasal infection of K18 human ACE2 transgenic mice (K18-hACE2) with SARS-CoV-2 resulted in lung pathology associated with viral replication and immune cell infiltration. In addition, ∼50% of infected mice exhibited CNS infection characterized by wide-spread viral replication in neurons accompanied by increased expression of chemokine ( Cxcl9, Cxcl10, Ccl2, Ccl5 and Ccl19 ) and cytokine ( Ifn-λ and Tnf-α ) transcripts associated with microgliosis and a neuroinflammatory response consisting primarily of monocytes/macrophages. Microglia depletion via administration of colony-stimulating factor 1 receptor inhibitor, PLX5622, in SARS-CoV-2 infected mice did not affect survival or viral replication but did result in dampened expression of proinflammatory cytokine/chemokine transcripts and a reduction in monocyte/macrophage infiltration. These results argue that microglia are dispensable in terms of controlling SARS-CoV-2 replication in in the K18-hACE2 model but do contribute to an inflammatory response through expression of pro-inflammatory genes. Collectively, these findings contribute to previous work demonstrating the ability of SARS-CoV-2 to infect neurons as well as emphasizing the potential use of the K18-hACE2 model to study immunological and neuropathological aspects related to SARS-CoV-2-induced neurologic disease. Importance Understanding the immunological mechanisms contributing to both host defense and disease following viral infection of the CNS is of critical importance given the increasing number of viruses that are capable of infecting and replicating within the nervous system. With this in mind, the present study was undertaken to evaluate the role of microglia in aiding in host defense following experimental infection of the central nervous system (CNS) of K18-hACE2 with SARS-CoV-2, the causative agent of COVID-19. Neurologic symptoms that range in severity are common in COVID-19 patients and understanding immune responses that contribute to restricting neurologic disease can provide important insight into better understanding consequences associated with SARS-CoV-2 infection of the CNS.

Neurologic Therapeutics in 2035

Therapeutic development has accelerated rapidly in the past 5 years in many neurologic and neurodegenerative diseases. The therapeutic categories of development include small molecules, genetic therapies, and cell-based therapies. Current development has provided novel treatment approaches to disorders without available treatment. However, the regulatory procedures to allow for access to these therapies is challenging, as is the ability to provide wide access to increasingly expensive therapies. By 2035, these challenges are likely to have accelerated and have the potential to create bottlenecks in drug approval and reduced access to patients. Innovative regulatory and payer solutions are required. In addition, ethical considerations around genetic therapies should be considered in current and future development. These approaches will ensure that patients with neurologic disease have broad access to highly innovative therapies.

Microdialysis and microperfusion electrodes in neurologic disease monitoring

Contemporary biomarker collection techniques in blood and cerebrospinal fluid have to date offered only modest clinical insights into neurologic diseases such as epilepsy and glioma. Conversely, the collection of human electroencephalography (EEG) data has long been the standard of care in these patients, enabling individualized insights for therapy and revealing fundamental principles of human neurophysiology. Increasing interest exists in simultaneously measuring neurochemical biomarkers and electrophysiological data to enhance our understanding of human disease mechanisms. This review compares microdialysis, microperfusion, and implanted EEG probe architectures and performance parameters. Invasive consequences of probe implantation are also investigated along with the functional impact of biofouling. Finally, previously developed microdialysis electrodes and microperfusion electrodes are reviewed in preclinical and clinical settings. Critically, current and precedent microdialysis and microperfusion probes lack the ability to collect neurochemical data that is spatially and temporally coincident with EEG data derived from depth electrodes. This ultimately limits diagnostic and therapeutic progress in epilepsy and glioma research. However, this gap also provides a unique opportunity to create a dual-sensing technology that will provide unprecedented insights into the pathogenic mechanisms of human neurologic disease.

Neurology in a Changing Climate: A Scoping Review

Importance: Although the international community collectively seeks to reduce global temperature rise to less than 1.5C, there are already irreversible environmental changes that have occurred, and currently available evidence suggests these changes will continue to occur. As we begin to witness the effects of a warming planet on human health, it is imperative that as neurologists we anticipate the ways in which the epidemiology and incidence of neurologic disease may be affected. Objective: In this review, we organize our analysis around three key themes related to climate change and neurologic health: extreme weather events and temperature fluctuations, emerging neuro-infectious diseases, and pollutant impacts. Across each of these key themes, we appraise and review recent literature relevant to neurological disease and the practice of neurology. Evidence Review: Studies were identified using a set of relevant search terms relating to climate change and neurologic diseases in the PubMed repository for publications between 1990 and 2021. Studies were included if they pertained to human incidence or prevalence of disease, were in the English language, and were relevant to neurologic disease. Findings: We identified a total of 136 articles, grouped into the three key themes of our study; extreme weather events and temperature fluctuations (23 studies), emerging neuro-infectious diseases (42 studies), and pollutant impacts (71 studies). Broadly, the studies included highlighted the relationships between neurologic symptom exacerbation and temperature variability, tick-borne infections and warming climates, and airborne pollutants and cerebrovascular disease incidence and severity. Conclusions and Relevance: Our work highlights three key priorities for further work; namely, neuro-infectious disease risk mitigation, an understanding of the pathophysiology of airborne pollutants on the nervous system, and research into how to improve delivery of neurologic care in the face of climate-related disruptions.

Autonomic Disorders

A practical but arbitrary classification of autonomic disorders is used at Mayo Clinic. Presented in a modified and abbreviated form in this chapter, that classification serves to organize and provide an overview of autonomic disorders. It is organized by anatomical systems and levels, although some syndromes and disorders do not fit neatly into this organization and therefore are assigned their own category. This classification quickly shows how abundant and interspersed autonomic dysfunction is among various categories of neurologic disease. Therefore, the role of this chapter is not to describe every disorder that can be associated with autonomic dysfunction. Rather, the chapter focuses on disorders with autonomic dysfunction as a predominant or important feature and thereby covers what are generally referred to as autonomic disorders.

Extracellular miRNA biomarkers in neurologic disease: is cerebrospinal fluid helpful?

Aim: The aim of our work is to aggregate data from publications of cerebrospinal fluid extracellular miRNA to identify candidate diagnostic biomarkers, and those warranting further study. Materials & methods: Data were pooled from nine studies, encompassing 864 patients across 16 diseases. Unsupervised clustering grouped patients by a broad category of diseases. Results & conclusion: Compared with healthy controls, in patients with Alzheimer’s disease, hsa-miR-767-5p was overexpressed (p < 0.001) and in patients with Huntington’s disease, hsa-miR-361-3p was underexpressed (p < 10-4). We also define a subset of extracellular miRNA as candidate biomarkers that are robustly detected across patients, studies and diseases; thereby, warranting further study.