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A 10-year-old girl presented with ileus, urinary retention, dry mouth, lack of tears, fixed dilated pupils, and diffuse anhidrosis 7-days after a febrile illness. We hypothesized that her syndrome was due to autoimmunity against muscarinic acetylcholine receptors, blocking their activation. Using an indirect enzyme-linked immunosorbent assay for all five muscarinic receptors (M₁ -M₅ ) we identified in the patient's serum antibodies that selectively bound to M₃ receptors. In-vitro functional studies confirmed that these autoantibodies selectively blocked M₃ receptor activation. Thus, autoantibodies against M₃ acetylcholine receptors can cause acute postganglionic cholinergic dysautonomia. This article is protected by copyright. All rights reserved.

Medical services can be conceptualized as falling into two categories: procedures and cognitive care. A procedure is defined as a surgical, medical, or diagnostic test performed on a patient, such as an x-ray, wound suture, surgery, or physical therapy treatment. Cognitive care, also known as Evaluation and Management (E/M) services, involves performing a medical history along with a physical examination and possibly ordering or reviewing diagnostic tests before formulating a medical opinion and initiating a care plan. The uniform language and categorization of all medical services is contained in the Current Procedural Terminology (CPT) manual by the American Medical Association, which precisely describes all medical services using non-overlapping definitions and descriptions. The codes defined by CPT are the most commonly accepted set of codes used to file medical claims. In 2000, the US Department of Health and Human Services designated CPT to be the national reporting standard used in conjunction with the Health Insurance Portability and Accountability Act (HIPAA). CPT codes used today for E/M services were established in 1995 and define the components of history, examination, and medical decision making necessary to determine the level of each cognitive care service as delivered by a physician or other qualified health care professionals (eg, advanced practice providers). E/M rules were modified in 1997 and allowed some specialty services, such as neurology, to substitute a single system examination for a general, multisystem physical examination. Although new E/M codes were added over the years, the code descriptions and documentation guidelines for E/M services for outpatient and inpatient care remained essentially unchanged from 1997 through 2020. Most of the work performed by neurologists is E/M services, and the rules for coding outpatient care will change dramatically on January 1, 2021. This article discusses the rationale for these coding changes and explains how they are to be applied in the clinical setting.

PURPOSE/OBJECTIVE:Obstructive sleep apnea (OSA) is independently associated with increased risk for stroke and other cardiovascular diseases. Since activated platelets play an important role in cardiovascular disease, the objective of this study was to determine whether platelet reactivity was altered in OSA subjects with intermittent nocturnal hypoxemia. METHODS:Thirty-one subjects, without hypertension or cardiovascular disease and not taking medication, participated in the study. Subjects were stratified based on OSA-related oxygen desaturation index (ODI) recorded during overnight polysomnography. Platelet reactivity to a broad panel of agonists (collagen, thrombin, protease-activated receptor1 hexapeptide, epinephrine, ADP) was measured by monitoring platelet aggregation and ATP secretion. Expression of platelet activation markers CD154 (CD40L) and CD62P (P-selectin) and platelet-monocyte aggregates (PMA) was quantified by flow cytometry. RESULTS:Epinephrine-induced platelet aggregation was substantially decreased in OSA subjects with significant intermittent hypoxemia (ODI ≥ 15) compared with subjects with milder hypoxemia levels (ODI < 15) (area under curve, p = 0.01). In addition, OSA subjects with ODI ≥ 15 exhibited decreased thrombin-induced platelet aggregation (p = 0.02) and CD40L platelet surface expression (p = 0.05). Platelet responses to the other agonists, CD62P platelet surface expression, and PMA levels were not significantly different between groups. Reduction in platelet responses to epinephrine and thrombin, and decreased CD40L surface marker expression in significant hypoxemic OSA individuals, is consistent with their platelets being in an activated state. CONCLUSIONS:Increased platelet activation was present in otherwise healthy subjects with intermittent nocturnal hypoxemia due to underlying OSA. This prothrombotic milieu in the vasculature is likely a key contributing factor toward development of thrombosis and cardiovascular disease. TRIAL REGISTRATION/BACKGROUND:NCT00859950.

The COVID-19 pandemic has caused global anguish unparalleled in recent times. As cases rise, increased pressure on health services, combined with severe disruption to people's everyday lives, can adversely affect individuals living with chronic illnesses, including people with epilepsy. Stressors related to disruption to healthcare, finances, mental well-being, relationships, schooling, physical activity, and increased isolation could increase seizures and impair epilepsy self-management. We aim to understand the impact that COVID-19 has had on the health and well-being of people with epilepsy focusing on exposure to increased risk of seizures, associated comorbidity, and mortality. We designed two online surveys with one addressing people with epilepsy directly and the second for caregivers to report on behalf of a person with epilepsy. The survey is ongoing and has yielded 463 UK-based responses by the end of September 2020. Forty percent of respondents reported health changes during the pandemic (n = 185). Respondents cited a change in seizures (19%, n = 88), mental health difficulties (34%, n = 161), and sleep disruption (26%, n = 121) as the main reasons. Thirteen percent found it difficult to take medication on time. A third had difficulty accessing medical services (n = 154), with 8% having had an appointment canceled (n = 39). Only a small proportion reported having had discussions about epilepsy-related risks, such as safety precautions (16%, n = 74); mental health (29%, n = 134); sleep (30%, n = 140); and Sudden Unexpected Death in Epilepsy (SUDEP; 15%, n = 69) in the previous 12 months. These findings suggest that people with epilepsy are currently experiencing health changes, coupled with inadequate access to services. Also, there seems to be a history of poor risk communication in the months preceding the pandemic. As the UK witnesses a second COVID-19 wave, those involved in healthcare delivery must ensure optimal care is provided for people with chronic conditions, such as epilepsy, to ensure that avoidable morbidity and mortality is prevented during the pandemic, and beyond.

There are an estimated 10 000 monogenic diseases affecting tens of millions of individuals worldwide. The application of CRISPR/Cas genome editing tools to treat monogenic diseases is an emerging strategy with the potential to generate personalized treatment approaches for these patients. CRISPR/Cas-based systems are programmable and sequence-specific genome editing tools with the capacity to generate base pair resolution manipulations to DNA or RNA. The complexity of genomic insults resulting in heritable disease requires patient-specific genome editing strategies with consideration of DNA repair pathways, and CRISPR/Cas systems of different types, species, and those with additional enzymatic capacity and/or delivery methods. In this review we aim to discuss broad and multifaceted therapeutic applications of CRISPR/Cas gene editing systems including in harnessing of homology directed repair, non-homologous end joining, microhomology-mediated end joining, and base editing to permanently correct diverse monogenic diseases.

Sleep spindles are functionally important NREM sleep EEG oscillations which are generated in thalamocortical, corticothalamic and possibly cortico-cortical circuits. Previous hypotheses suggested that slow and fast spindles or spindles with various spatial extent may be generated in different circuits with various cortical laminar innervation patterns. We used NREM sleep EEG data recorded from four human epileptic patients undergoing presurgical electrophysiological monitoring with subdural electrocorticographic grids (ECoG) and implanted laminar microelectrodes penetrating the cortex (IME). The position of IMEs within cortical layers was confirmed using postsurgical histological reconstructions. Many spindles detected on the IME occurred only in one layer and were absent from the ECoG, but with increasing amplitude simultaneous detection in other layers and on the ECoG became more likely. ECoG spindles were in contrast usually accompanied by IME spindles. Neither IME nor ECoG spindle cortical profiles were strongly associated with sleep spindle frequency or globality. Multiple-unit and single-unit activity during spindles, however, was heterogeneous across spindle types, but also across layers and subjects. Our results indicate that extremely local spindles may occur in any cortical layer, but co-occurrence at other locations becomes likelier with increasing amplitude and the relatively large spindles detected on ECoG channels have a stereotypical laminar profile. We found no compelling evidence that different spindle types are associated with different laminar profiles, suggesting that they are generated in cortical and thalamic circuits with similar cortical innervation patterns. Local neuronal activity is a stronger candidate mechanism for driving functional differences between spindles subtypes.

Multiple neuro-ophthalmological manifestations have been described in association with COVID-19. These symptoms and signs may be the result of a range of pathophysiological mechanisms throughout the course from acute illness to recovery phase. Optic nerve dysfunction, eye movement abnormalities and visual field defects have been described.