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      Dysautonomia following Lyme disease: a key component of post-treatment Lyme disease syndrome?

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          Abstract

          Dysautonomia, or dysfunction of the autonomic nervous system (ANS), may occur following an infectious insult and can result in a variety of debilitating, widespread, and often poorly recognized symptoms. Dysautonomia is now widely accepted as a complication of COVID-19 and is an important component of Post-Acute Sequelae of COVID-19 (PASC or long COVID). PASC shares many overlapping clinical features with other infection-associated chronic illnesses including Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Post-Treatment Lyme Disease Syndrome (PTLDS), suggesting that they may share common underlying mechanisms including autonomic dysfunction. Despite the recognition of this complication of Lyme disease in the care of patients with PTLD, there has been a scarcity of research in this field and dysautonomia has not yet been established as a complication of Lyme disease in the medical literature. In this review, we discuss the evidence implicating Borrelia burgdorferi as a cause of dysautonomia and the related symptoms, propose potential pathogenic mechanisms given our knowledge of Lyme disease and mechanisms of PASC and ME/CFS, and discuss the diagnostic evaluation and treatments of dysautonomia. We also outline gaps in the literature and priorities for future research.

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          Most cited references132

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          Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin.

          Vertebrates achieve internal homeostasis during infection or injury by balancing the activities of proinflammatory and anti-inflammatory pathways. Endotoxin (lipopolysaccharide), produced by all gram-negative bacteria, activates macrophages to release cytokines that are potentially lethal. The central nervous system regulates systemic inflammatory responses to endotoxin through humoral mechanisms. Activation of afferent vagus nerve fibres by endotoxin or cytokines stimulates hypothalamic-pituitary-adrenal anti-inflammatory responses. However, comparatively little is known about the role of efferent vagus nerve signalling in modulating inflammation. Here, we describe a previously unrecognized, parasympathetic anti-inflammatory pathway by which the brain modulates systemic inflammatory responses to endotoxin. Acetylcholine, the principle vagal neurotransmitter, significantly attenuated the release of cytokines (tumour necrosis factor (TNF), interleukin (IL)-1beta, IL-6 and IL-18), but not the anti-inflammatory cytokine IL-10, in lipopolysaccharide-stimulated human macrophage cultures. Direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock.
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            Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19

            Coronavirus disease 2019 (COVID-19) is a clinical syndrome caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with severe disease show hyperactivation of the immune system, which can affect multiple organs besides the lungs. Here, we propose that SARS-CoV-2 infection induces a process known as immunothrombosis, in which activated neutrophils and monocytes interact with platelets and the coagulation cascade, leading to intravascular clot formation in small and larger vessels. Microthrombotic complications may contribute to acute respiratory distress syndrome (ARDS) and other organ dysfunctions. Therapeutic strategies aimed at reducing immunothrombosis may therefore be useful. Several antithrombotic and immunomodulating drugs have been proposed as candidates to treat patients with SARS-CoV-2 infection. The growing understanding of SARS-CoV-2 infection pathogenesis and how it contributes to critical illness and its complications may help to improve risk stratification and develop targeted therapies to reduce the acute and long-term consequences of this disease.
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              The vagus nerve and the inflammatory reflex--linking immunity and metabolism.

              The vagus nerve has an important role in regulation of metabolic homeostasis, and efferent vagus nerve-mediated cholinergic signalling controls immune function and proinflammatory responses via the inflammatory reflex. Dysregulation of metabolism and immune function in obesity are associated with chronic inflammation, a critical step in the pathogenesis of insulin resistance and type 2 diabetes mellitus. Cholinergic mechanisms within the inflammatory reflex have, in the past 2 years, been implicated in attenuating obesity-related inflammation and metabolic complications. This knowledge has led to the exploration of novel therapeutic approaches in the treatment of obesity-related disorders.

                Author and article information

                Contributors
                Journal
                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                1664-2295
                08 February 2024
                2024
                : 15
                : 1344862
                Affiliations
                [1] 1Division of Rheumatology, Johns Hopkins University , Baltimore, MD, United States
                [2] 2Department of Physical Medicine and Rehabilitation, Johns Hopkins University , Baltimore, MD, United States
                [3] 3Department of Pediatrics, Johns Hopkins University , Baltimore, MD, United States
                Author notes

                Edited by: Ilene Sue Ruhoy, Mount Sinai South Nassau, United States

                Reviewed by: Etheresia Pretorius, Stellenbosch University, South Africa

                Bruce Patterson, IncellDx Inc, United States

                Timothy Flanigan, Brown University, United States

                Nevena Zubcevik, Independent Researcher, Palo Alto, CA, United States

                Tania Dempsey, Aim Center for Personalized Medicine, United States

                *Correspondence: Brittany L. Adler brit.adler@ 123456jhmi.edu
                Article
                10.3389/fneur.2024.1344862
                10883079
                38390594
                47f1c909-f91a-4ca1-8fde-b3bc18f9d0ac
                Copyright © 2024 Adler, Chung, Rowe and Aucott.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 26 November 2023
                : 22 January 2024
                Page count
                Figures: 1, Tables: 2, Equations: 0, References: 133, Pages: 12, Words: 10372
                Funding
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Jerome L. Greene Foundation.
                Categories
                Neurology
                Review
                Custom metadata
                Autonomic Disorders

                Neurology
                dysautonomia,post-treatment lyme disease (ptld),postural orthostatic tachycardia syndrome (pots),borrelia (borreliella) burgdorferi,lyme disease

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