This article discusses the clinical presentation, evaluation, and management of the patient with optic neuritis. Initial emphasis is placed on clinical history, examination, diagnostic testing, and ...medical decision making, while subsequent focus is placed on examining specific inflammatory optic neuropathies. Clinical clues, examination findings, neuroimaging, and laboratory testing that differentiate autoimmune, granulomatous, demyelinating, infectious, and paraneoplastic causes of optic neuritis are assessed, and current treatments are evaluated.
Advances in technology and immunology have enhanced our understanding of the pathologies driving inflammatory optic nerve injury. Clinicians are now able to interrogate optic nerve structure and function during inflammatory injury, rapidly identify disease-relevant autoimmune targets, and deliver timely therapeutics to improve visual outcomes.
Optic neuritis is a common clinical manifestation of central nervous system inflammation. Depending on the etiology, visual prognosis and the risk for recurrent injury may vary. Rapid and accurate diagnosis of optic neuritis may be critical for limiting vision loss, future neurologic disability, and organ damage. This article will aid neurologists in formulating a systematic approach to patients with optic neuritis.
Neuromyelitis optica (NMO) is an autoimmune disease of the CNS that is characterized by inflammatory demyelinating lesions in the spinal cord and optic nerve, potentially leading to paralysis and ...blindness. NMO can usually be distinguished from multiple sclerosis (MS) on the basis of seropositivity for IgG antibodies against the astrocytic water channel aquaporin-4 (AQP4). Differentiation from MS is crucial, because some MS treatments can exacerbate NMO. NMO pathogenesis involves AQP4-IgG antibody binding to astrocytic AQP4, which causes complement-dependent cytotoxicity and secondary inflammation with granulocyte and macrophage infiltration, blood-brain barrier disruption and oligodendrocyte injury. Current NMO treatments include general immunosuppressive agents, B-cell depletion, and plasma exchange. Therapeutic strategies targeting complement proteins, the IL-6 receptor, neutrophils, eosinophils and CD19--all initially developed for other indications--are under clinical evaluation for repurposing for NMO. Therapies in the preclinical phase include AQP4-blocking antibodies and AQP4-IgG enzymatic inactivation. Additional, albeit currently theoretical, treatment options include reduction of AQP4 expression, disruption of AQP4 orthogonal arrays, enhancement of complement inhibitor expression, restoration of the blood-brain barrier, and induction of immune tolerance. Despite the many therapeutic options in NMO, no controlled clinical trials in patients with this condition have been conducted to date.
Satralizumab, a humanised monoclonal antibody targeting the interleukin-6 receptor, reduced the risk of relapse in patients with neuromyelitis optica spectrum disorder (NMOSD) when added to ...immunosuppressant therapy. This study assessed the safety and efficacy of satralizumab monotherapy in patients with the disorder.
In this phase 3, double-blind, placebo-controlled, parallel-group trial, we enrolled adults aged 18–74 years with aquaporin-4 antibody seropositive or seronegative NMOSD at 44 investigational sites in 13 countries. Eligible participants had experienced at least one documented NMOSD attack or relapse in the past 12 months and had a score of 6·5 or less on the Expanded Disability Status Scale. Exclusion criteria included clinical relapse 30 days or fewer before baseline. Participants were randomly assigned (2:1) to receive satralizumab 120 mg or visually matched placebo subcutaneously at weeks 0, 2, 4, and every 4 weeks thereafter. Taking immunosuppressants concomitantly was prohibited. The primary endpoint was time to the first protocol-defined relapse, based on the intention-to-treat population and analysed with stratification for two randomisation factors (previous therapy for prevention of attacks and nature of the most recent attack). Safety was assessed in all participants who received at least one dose of satralizumab or placebo. The double-blind phase was due to last until 44 protocol-defined relapses occurred or 1·5 years after random assignment of the last patient enrolled, whichever occurred first; participants could enter an open-label phase after the occurrence of a protocol-defined relapse or at the end of the double-blind phase. The study is registered with ClinicalTrials.gov, NCT02073279.
95 (57%) of 168 screened participants were randomly assigned to treatment (63 to satralizumab; 32 to placebo) between Aug 5, 2014, and April 2, 2017. Protocol-defined relapses occurred in 19 (30%) patients receiving satralizumab and 16 (50%) receiving placebo (hazard ratio 0·45, 95% CI 0·23–0·89; p=0·018). 473·9 adverse events per 100 patient-years occurred in the satralizumab group, as did 495·2 per 100 patient-years in the placebo group; the incidence of serious adverse events and adverse events leading to withdrawal was similar between groups.
Satralizumab monotherapy reduced the rate of NMOSD relapse compared with placebo in the overall trial population, with a favourable safety profile. The patient population included a ratio of aquaporin-4 antibody seropositive and seronegative patients that was reflective of clinical practice. Satralizumab has the potential to become a valuable treatment option for patients with NMOSD.
Chugai Pharmaceutical (Roche).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Breakdown of myelin sheaths is a pathological hallmark of several autoimmune diseases of the nervous system. We employed autoantibody-mediated animal models of demyelinating diseases, including a rat ...model of neuromyelitis optica (NMO), to target myelin and found that myelin lamellae are broken down into vesicular structures at the innermost region of the myelin sheath. We demonstrated that myelin basic proteins (MBP), which form a polymer in between the myelin membrane layers, are targeted in these models. Elevation of intracellular Ca2+ levels resulted in MBP network disassembly and myelin vesiculation. We propose that the aberrant phase transition of MBP molecules from their cohesive to soluble and non-adhesive state is a mechanism triggering myelin breakdown in NMO and possibly in other demyelinating diseases.
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•Characterization of myelin sheath pathology close its native state•Vesiculation of inner sheath layers is a common feature of myelin pathology•Loss of MBP function triggers myelin vesiculation•Elevation of intracellular Ca2+ triggers MBP phase transition
Using high-pressure freezing and electron microscopy, Weil et al. show that that the vesicular disruption of the myelin sheath is a common feature of myelin degeneration in demyelinating diseases. The authors suggest that the underlying mechanism is the aberrant transition of MBP molecules from their cohesive state to their non-adhesive state.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A critical study of diabetes in the popular imagination
Over twenty-nine million people in the United States, more than nine percent of the population, have some form of diabetes. In Managing ...Diabetes, Jeffrey A. Bennett focuses on how the disease is imagined in public culture. Bennett argues that popular anecdotes, media representation, and communal myths are as meaningful as medical and scientific understandings of the disease.
In focusing on the public character of the disease, Bennett looks at health campaigns and promotions as well as the debate over public figures like Sonia Sotomayor and her management of type 1 diabetes. Bennett examines the confusing and contradictory public depictions of diabetes to demonstrate how management of the disease is not only clinical but also cultural. Bennett also has type 1 diabetes and speaks from personal experience about the many misunderstandings and myths that are alive in the popular imagination. Ultimately, Managing Diabetes offers a fresh take on how disease is understood in contemporary society and the ways that stigma, fatalism, and health can intersect to shape diabetes’s public character. This disease has dire health implications, and rates keep rising. Bennett argues that until it is better understood it cannot be better treated.
Serum antibodies directed against myelin oligodendrocyte glycoprotein (MOG) are found in patients with acquired CNS demyelinating syndromes that are distinct from multiple sclerosis and ...aquaporin-4-seropositive neuromyelitis optica spectrum disorder. Based on an extensive literature review and a structured consensus process, we propose diagnostic criteria for MOG antibody-associated disease (MOGAD) in which the presence of MOG-IgG is a core criterion. According to our proposed criteria, MOGAD is typically associated with acute disseminated encephalomyelitis, optic neuritis, or transverse myelitis, and is less commonly associated with cerebral cortical encephalitis, brainstem presentations, or cerebellar presentations. MOGAD can present as either a monophasic or relapsing disease course, and MOG-IgG cell-based assays are important for diagnostic accuracy. Diagnoses such as multiple sclerosis need to be excluded, but not all patients with multiple sclerosis should undergo screening for MOG-IgG. These proposed diagnostic criteria require validation but have the potential to improve identification of individuals with MOGAD, which is essential to define long-term clinical outcomes, refine inclusion criteria for clinical trials, and identify predictors of a relapsing versus a monophasic disease course.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Recent advances in machine learning (ML) and artificial intelligence have provided an exciting opportunity to computerize the fundamental and applied studies of complex reaction systems via ...self-driving laboratories. Autonomous robotic experimentation can enable time-, material-, and resource-efficient exploration and/or optimization of high-dimensional space reaction systems. Furthermore, interpretation of the ML models trained on the experimental data can unveil the underlying reaction mechanisms. In this article, we discuss different elements of a self-driving lab, and present recent efforts in autonomous reaction modeling and optimization. Further development and adoption of ML-guided closed-loop experimentation strategies can realize the full potential of autonomous chemical science and engineering to accelerate the discovery and development of advanced materials and molecules.
•An overview of the elements of self-driving laboratories.•Recent advancements in autonomous chemical science and engineering.•Recent progress in closed-loop autonomous reaction modeling and optimization.•Future opportunities in surrogate model-based reaction exploration.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Neuromyelitis optica (NMO) is an inflammatory CNS syndrome distinct from multiple sclerosis (MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). Prior NMO diagnostic ...criteria required optic nerve and spinal cord involvement but more restricted or more extensive CNS involvement may occur. The International Panel for NMO Diagnosis (IPND) was convened to develop revised diagnostic criteria using systematic literature reviews and electronic surveys to facilitate consensus. The new nomenclature defines the unifying term NMO spectrum disorders (NMOSD), which is stratified further by serologic testing (NMOSD with or without AQP4-IgG). The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable. The IPND also proposed validation strategies and achieved consensus on pediatric NMOSD diagnosis and the concepts of monophasic NMOSD and opticospinal MS.
This essay explores how public reception of, and individual resistance to, public health mandates have reinforced agentic notions of bodily management in the COVID-19 era. Our collective approach to ...the pandemic continues to secure prevalent understandings of human agency over disease and illness by reifying the concept of personal choice. Notions of risk and shame shape these performances but do little to dislodge cultural frames that reify notions of individualism and the entrepreneurial subject. The wide circulation of viral videos highlighting the defiance of mask mandates is one site where choice and personal autonomy animate these debates. These confrontational acts are not easily segmented from the other cultural apparatuses where the privatization of risk is marshalled for political ends.
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