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New Challenges and Perspectives in Neurology and Autonomic Disorders
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New Challenges and Perspectives in Neurology and Autonomic Disorders

A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Clinical Medicine, Cell, and Organism Physiology".

Deadline for manuscript submissions: closed (10 July 2024) | Viewed by 87853

Special Issue Editors

Dr. Svetlana Blitshteyn

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Guest Editor
Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
Interests: neurology; autonomic disorders; POTS; long COVID; small fiber neuropathy; headaches; autoimmunity; immunotherapy
Dr. Ilene Ruhoy

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Guest Editor
Mount Sinai South Chiari EDS Center, Oceanside, NY, USA
Interests: neurology; EDS; long COVID; headache; CSF leak; autoimmunity; chronic pain; connective tissue
Dr. Jennifer Robblee

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Guest Editor
Barrow Neurological Institute, Phoenix, AZ, USA
Interests: neurology; headaches; migraine; refractory migraine; status migrainosus

Special Issue Information

Dear Colleagues,

The autonomic nervous system, consisting of sympathetic, parasympathetic and enteric divisions, is an integral part of the central and peripheral nervous systems and controls homeostasis, blood flow and responses to internal and external stimuli. Disorders of the autonomic nervous system—both common, such as POTS, neurocardiogenic syncope and orthostatic hypotension; and rare, such as multiple system atrophy, amyloid neuropathy and familial dysautonomia—have been an evolving area of research in basic and translational science as well as in clinical practice. More recently, the SARS-CoV-2 pandemic further underscored the need to elucidate the neurologic and autonomic mechanisms of post-infectious syndromes. To this end, the new frontier in neurology and autonomic disorders, as well as the mechanistic interplay between a wide range of neurologic conditions and autonomic dysfunctions, present an exciting opportunity for groundbreaking discoveries. With this Special Issue of Journal of Personalized Medicine, we aim to gather original research, reviews and short communications on a variety of topics involving neurologic and autonomic disorders and encompassing, but not limited to, the following subspecialties: autonomic disorders, headache medicine, neuromuscular and movement disorders, neurodegenerative disorders, neuroimmunology, pediatric neurology, neurocardiology, neuropathology, neuroimaging, neurologic and autonomic manifestations of systemic disease, and post-COVID-19 neurologic and autonomic manifestations. Studies and reviews of the potential biomarkers and identification of effective diagnostic and therapeutic approaches in patients with complex neurologic and autonomic disorders would be of particular interest to us in terms of advancing our understanding of these disorders, in addition to helping us expand our diagnostic and therapeutic capabilities in clinical practice.

Dr. Svetlana Blitshteyn
Dr. Ilene Ruhoy
Dr. Jennifer Robblee
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Personalized Medicine is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurology
  • autonomic disorders
  • POTS
  • long COVID
  • dysautonomia
  • orthostatic intolerance
  • personalized medicine
  • autoimmunity

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review, Other

5 pages, 151 KiB  
Editorial
New Challenges and Perspectives in Neurology and Autonomic Disorders: A Leap Forward
by Svetlana Blitshteyn and Ilene Ruhoy
J. Pers. Med. 2024, 14(10), 1063; https://doi.org/10.3390/jpm14101063 - 16 Oct 2024
Viewed by 1565
Abstract
“Nothing in life is to be feared, it is only to be understood [...] Full article
(This article belongs to the Special Issue New Challenges and Perspectives in Neurology and Autonomic Disorders)

Research

Jump to: Editorial, Review, Other

10 pages, 251 KiB  
Article
The Presence of Ganglionic Acetylcholine Receptor Antibodies in Sera from Patients with Functional Gastrointestinal Disorders: A Preliminary Study
by Shunya Nakane, Akihiro Mukaino, Yoshiaki Okumura, Hiroaki Hirosawa, Osamu Higuchi, Hidenori Matsuo, Mosaburo Kainuma and Yuji Nakatsuji
J. Pers. Med. 2024, 14(5), 485; https://doi.org/10.3390/jpm14050485 - 30 Apr 2024
Viewed by 1733
Abstract
Background: Functional gastrointestinal disorders (FGIDs), including functional dyspepsia (FD) and irritable bowel syndrome (IBS), are characterized by chronic and recurrent gastrointestinal symptoms. Clinically, FD and IBS often resemble gastrointestinal dysmotility caused by autoimmune autonomic neuropathy. We examined the seropositive frequency of autoantibodies against [...] Read more.
Background: Functional gastrointestinal disorders (FGIDs), including functional dyspepsia (FD) and irritable bowel syndrome (IBS), are characterized by chronic and recurrent gastrointestinal symptoms. Clinically, FD and IBS often resemble gastrointestinal dysmotility caused by autoimmune autonomic neuropathy. We examined the seropositive frequency of autoantibodies against ganglionic nicotinic acetylcholine receptors (gnAChRs) in patients presenting with FGIDs. Objective: To elucidate the seropositivity of gnAChR antibodies and the clinical features of seropositive FD and IBS. Materials and Methods: We measured autoantibodies against the gnAChR α3 and β4subunits using luciferase immunoprecipitation systems. Serum samples from patients with any autonomic symptoms were obtained from hospitals in Japan between January 2012 and August 2018 (1787 serum samples of 1381 patients). We selected FD and IBS patients and compared the clinical characteristics and prevalence of autonomic symptoms between those with seropositive and seronegative IBS and FD. Results: Nine IBS and two FD cases (one comorbid case with IBS) were found. We found four patients (36.4%) in whom gnAChR antibodies were positive in these eleven patients. Sicca symptoms were observed in three of four cases (75%) of seropositive FGID compared with zero of seven cases (0%) of seronegative FGID. Conclusions: We found patients with gnAChR antibodies in FD and IBS patients. These data will be valuable for elucidating the pathophysiology of these FGIDs and developing new treatment strategies. Full article
(This article belongs to the Special Issue New Challenges and Perspectives in Neurology and Autonomic Disorders)
8 pages, 211 KiB  
Communication
The Head-Up Tilt Table Test as a Measure of Autonomic Functioning among Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by Leonard A. Jason, William J. McGarrigle and Ruud C. W. Vermeulen
J. Pers. Med. 2024, 14(3), 238; https://doi.org/10.3390/jpm14030238 - 23 Feb 2024
Viewed by 4961
Abstract
Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) often experience autonomic symptoms. In the present study, we evaluated 193 adults seeking treatment for ME/CFS, who were recruited from an outpatient clinic. The participants completed a head-up tilt table test to assess two common types [...] Read more.
Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) often experience autonomic symptoms. In the present study, we evaluated 193 adults seeking treatment for ME/CFS, who were recruited from an outpatient clinic. The participants completed a head-up tilt table test to assess two common types of orthostatic intolerance, namely, postural orthostatic tachycardia syndrome (POTS) and orthostatic hypotension (OH). During the tilt test, 32.5% of the participants demonstrated POTS or OH. The participants with either of these two common types of orthostatic intolerance were found to have more problems with sleep and post-exertional malaise as assessed by the DePaul Symptom Questionnaire; these patients also reported more physical and health function limitations. The implications of the findings are discussed. Full article
(This article belongs to the Special Issue New Challenges and Perspectives in Neurology and Autonomic Disorders)
10 pages, 538 KiB  
Article
Dysautonomia, but Not Cardiac Dysfunction, Is Common in a Cohort of Individuals with Long COVID
by Laura Tabacof, Jamie Wood, Erica Breyman, Jenna Tosto-Mancuso, Amanda Kelly, Kaitlyn Wilkey, Chi Zhang, David Putrino and Amy Kontorovich
J. Pers. Med. 2023, 13(11), 1606; https://doi.org/10.3390/jpm13111606 - 14 Nov 2023
Viewed by 3022
Abstract
Despite the prevalence of dysautonomia in people with Long COVID, it is currently unknown whether Long COVID dysautonomia is routinely accompanied by structural or functional cardiac alterations. In this retrospective observational study, the presence of echocardiographic abnormalities was assessed. Left ventricular (LV) chamber [...] Read more.
Despite the prevalence of dysautonomia in people with Long COVID, it is currently unknown whether Long COVID dysautonomia is routinely accompanied by structural or functional cardiac alterations. In this retrospective observational study, the presence of echocardiographic abnormalities was assessed. Left ventricular (LV) chamber sizes were correlated to diagnostic categories and symptoms via standardized patient-reported outcome (PRO) questionnaires. A total of 203 individuals with Long COVID without pre-existing cardiac disease and with available echocardiograms were included (mean age, 45 years; 67% female). Overall, symptoms and PRO scores for fatigue, breathlessness, quality of life, disability, anxiety and depression were not different between those classified with post-COVID dysautonomia (PCD, 22%) and those unclassified (78%). An LV internal diameter at an end-diastole z score < −2 was observed in 33 (16.5%) individuals, and stroke volume (SV) was lower in the PCD vs. unclassified subgroup (51.6 vs. 59.2 mL, 95% C.I. 47.1–56.1 vs. 56.2–62.3). LV end-diastolic volume (mean diff. (95% CI) −13 [−1–−26] mL, p = 0.04) and SV (−10 [−1–−20] mL, p = 0.03) were smaller in those individuals reporting a reduction in physical activity post-COVID-19 infection, and smaller LVMI was weakly correlated with worse fatigue (r = 0.23, p = 0.02). The majority of individuals with Long COVID report shared symptoms and did not demonstrate cardiac dysfunction on echocardiography. Full article
(This article belongs to the Special Issue New Challenges and Perspectives in Neurology and Autonomic Disorders)
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14 pages, 420 KiB  
Article
Neuropsychiatric Manifestations of Mast Cell Activation Syndrome and Response to Mast-Cell-Directed Treatment: A Case Series
by Leonard B. Weinstock, Renee M. Nelson and Svetlana Blitshteyn
J. Pers. Med. 2023, 13(11), 1562; https://doi.org/10.3390/jpm13111562 - 31 Oct 2023
Cited by 2 | Viewed by 25926
Abstract
Mast cell activation syndrome (MCAS) is an immune disease with an estimated prevalence of 17%. Mast cell chemical mediators lead to heterogeneous multisystemic inflammatory and allergic manifestations. This syndrome is associated with various neurologic and psychiatric disorders, including headache, dysautonomia, depression, generalized anxiety [...] Read more.
Mast cell activation syndrome (MCAS) is an immune disease with an estimated prevalence of 17%. Mast cell chemical mediators lead to heterogeneous multisystemic inflammatory and allergic manifestations. This syndrome is associated with various neurologic and psychiatric disorders, including headache, dysautonomia, depression, generalized anxiety disorder, and many others. Although MCAS is common, it is rarely recognized, and thus, patients can suffer for decades. The syndrome is caused by aberrant mast cell reactivity due to the mutation of the controller gene. A case series is presented herein including eight patients with significant neuropsychiatric disorders that were often refractory to standard medical therapeutics. Five patients had depression, five had generalized anxiety disorder, and four had panic disorder. Other psychiatric disorders included attention-deficit hyperactivity disorder, obsessive compulsive disorder, phobias, and bipolar disorder. All eight patients were subsequently diagnosed with mast cell activation syndrome; six had comorbid autonomic disorders, the most common being postural orthostatic tachycardia syndrome; and four had hypermobile Ehlers-Danlos syndrome. All patients experienced significant improvements regarding neuropsychiatric and multisystemic symptoms after mast-cell-directed therapy. In neuropsychiatric patients who have systemic symptoms and syndromes, it is important to consider the presence of an underlying or comorbid MCAS. Full article
(This article belongs to the Special Issue New Challenges and Perspectives in Neurology and Autonomic Disorders)
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12 pages, 1926 KiB  
Article
At-Home Blood Pressure Measurements Provide Better Assessments of Orthostatic Hypotension in Parkinson’s Disease
by Chathurini V Fernando, Sarah Osborn and Malcolm Horne
J. Pers. Med. 2023, 13(9), 1324; https://doi.org/10.3390/jpm13091324 - 28 Aug 2023
Viewed by 1524
Abstract
Orthostatic hypotension (OH) is common in Parkinson’s Disease (PD). It is intermittent, exacerbated by stressors including meals, medications, and dehydration, and frequently is unrecognized. Although intermittent, assessment is usually by a single “in clinic” BP measurement. This study examines whether 10 home measurements [...] Read more.
Orthostatic hypotension (OH) is common in Parkinson’s Disease (PD). It is intermittent, exacerbated by stressors including meals, medications, and dehydration, and frequently is unrecognized. Although intermittent, assessment is usually by a single “in clinic” BP measurement. This study examines whether 10 home measurements are more sensitive in detecting OH than a single “in clinic” measurement. Participants (44 people with PD and 16 controls) were instructed to measure lying and standing BP at home. BP was measured on five consecutive days upon waking and before bedtime. Symptoms were also assessed using the Movement Disorder Society United Parkinson’s Disease Rating Scale and the Non-Motor Questionnaire. While a postural drop in systolic BP (≥20 mmHg) was recorded “in clinic” in thirteen of the forty-four PD participants, a postural drop was found in at least one of the ten home measurements in twenty-eight of the forty-four participants. Morning hypertension and variability in lying systolic BP was more common in these subjects than in those without a postural drop or the controls. A greater number of measurements of lying and standing BP are more likely to reveal orthostatic hypotension, variation in systolic BP, and hypertension than a single office measurement in people with PD. Full article
(This article belongs to the Special Issue New Challenges and Perspectives in Neurology and Autonomic Disorders)
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Review

Jump to: Editorial, Research, Other

18 pages, 3167 KiB  
Review
Long COVID Is Not a Functional Neurologic Disorder
by Todd E. Davenport, Svetlana Blitshteyn, Nicola Clague-Baker, David Davies-Payne, Glenn J. Treisman and Sarah F. Tyson
J. Pers. Med. 2024, 14(8), 799; https://doi.org/10.3390/jpm14080799 - 29 Jul 2024
Viewed by 14608
Abstract
Long COVID is a common sequela of SARS-CoV-2 infection. Data from numerous scientific studies indicate that long COVID involves a complex interaction between pathophysiological processes. Long COVID may involve the development of new diagnosable health conditions and exacerbation of pre-existing health conditions. However, [...] Read more.
Long COVID is a common sequela of SARS-CoV-2 infection. Data from numerous scientific studies indicate that long COVID involves a complex interaction between pathophysiological processes. Long COVID may involve the development of new diagnosable health conditions and exacerbation of pre-existing health conditions. However, despite this rapidly accumulating body of evidence regarding the pathobiology of long COVID, psychogenic and functional interpretations of the illness presentation continue to be endorsed by some healthcare professionals, creating confusion and inappropriate diagnostic and therapeutic pathways for people living with long COVID. The purpose of this perspective is to present a clinical and scientific rationale for why long COVID should not be considered as a functional neurologic disorder. It will begin by discussing the parallel historical development of pathobiological and psychosomatic/sociogenic diagnostic constructs arising from a common root in neurasthenia, which has resulted in the collective understandings of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and functional neurologic disorder (FND), respectively. We will also review the case definition criteria for FND and the distinguishing clinical and neuroimaging findings in FND vs. long COVID. We conclude that considering long COVID as FND is inappropriate based on differentiating pathophysiologic mechanisms and distinguishing clinical findings. Full article
(This article belongs to the Special Issue New Challenges and Perspectives in Neurology and Autonomic Disorders)
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16 pages, 271 KiB  
Review
Autoimmunity in Syndromes of Orthostatic Intolerance: An Updated Review
by Clarissa Pena, Abdelmoniem Moustafa, Abdel-Rhman Mohamed and Blair Grubb
J. Pers. Med. 2024, 14(4), 435; https://doi.org/10.3390/jpm14040435 - 20 Apr 2024
Cited by 2 | Viewed by 6409
Abstract
Orthostatic intolerance is a broad term that represents a spectrum of dysautonomic disorders, including postural orthostatic tachycardia syndrome (POTS) and orthostatic hypotension (OH), as manifestations of severe autonomic failure. While the etiology of orthostatic intolerance has not yet fully been uncovered, it has [...] Read more.
Orthostatic intolerance is a broad term that represents a spectrum of dysautonomic disorders, including postural orthostatic tachycardia syndrome (POTS) and orthostatic hypotension (OH), as manifestations of severe autonomic failure. While the etiology of orthostatic intolerance has not yet fully been uncovered, it has been associated with multiple underlying pathological processes, including peripheral neuropathy, altered renin–aldosterone levels, hypovolemia, and autoimmune processes. Studies have implicated adrenergic, cholinergic, and angiotensin II type I autoantibodies in the pathogenesis of orthostatic intolerance. Several case series have demonstrated that immunomodulation therapy resulted in favorable outcomes, improving autonomic symptoms in POTS and OH. In this review, we highlight the contemporary literature detailing the association of autoimmunity with POTS and OH. Full article
(This article belongs to the Special Issue New Challenges and Perspectives in Neurology and Autonomic Disorders)
12 pages, 284 KiB  
Review
How Sex Hormones Affect Migraine: An Interdisciplinary Preclinical Research Panel Review
by Frederick Godley III, John Meitzen, Hadas Nahman-Averbuch, Mary Angela O’Neal, David Yeomans, Nanette Santoro, Nina Riggins and Lars Edvinsson
J. Pers. Med. 2024, 14(2), 184; https://doi.org/10.3390/jpm14020184 - 7 Feb 2024
Cited by 6 | Viewed by 11789
Abstract
Sex hormones and migraine are closely interlinked. Women report higher levels of migraine symptoms during periods of sex hormone fluctuation, particularly during puberty, pregnancy, and perimenopause. Ovarian steroids, such as estrogen and progesterone, exert complex effects on the peripheral and central nervous systems, [...] Read more.
Sex hormones and migraine are closely interlinked. Women report higher levels of migraine symptoms during periods of sex hormone fluctuation, particularly during puberty, pregnancy, and perimenopause. Ovarian steroids, such as estrogen and progesterone, exert complex effects on the peripheral and central nervous systems, including pain, a variety of special sensory and autonomic functions, and affective processing. A panel of basic scientists, when challenged to explain what was known about how sex hormones affect the nervous system, focused on two hormones: estrogen and oxytocin. Notably, other hormones, such as progesterone, testosterone, and vasopressin, are less well studied but are also highlighted in this review. When discussing what new therapeutic agent might be an alternative to hormone therapy and menopause replacement therapy for migraine treatment, the panel pointed to oxytocin delivered as a nasal spray. Overall, the conclusion was that progress in the preclinical study of hormones on the nervous system has been challenging and slow, that there remain substantial gaps in our understanding of the complex roles sex hormones play in migraine, and that opportunities remain for improved or novel therapeutic agents. Manipulation of sex hormones, perhaps through biochemical modifications where its positive effects are selected for and side effects are minimized, remains a theoretical goal, one that might have an impact on migraine disease and other symptoms of menopause. This review is a call to action for increased interest and funding for preclinical research on sex hormones, their metabolites, and their receptors. Interdisciplinary research, perhaps facilitated by a collaborative communication network or panel, is a possible strategy to achieve this goal. Full article
(This article belongs to the Special Issue New Challenges and Perspectives in Neurology and Autonomic Disorders)

Other

18 pages, 4015 KiB  
Opinion
Possible Role of Fibrinaloid Microclots in Postural Orthostatic Tachycardia Syndrome (POTS): Focus on Long COVID
by Douglas B. Kell, Muhammed Asad Khan, Binita Kane, Gregory Y. H. Lip and Etheresia Pretorius
J. Pers. Med. 2024, 14(2), 170; https://doi.org/10.3390/jpm14020170 - 31 Jan 2024
Cited by 2 | Viewed by 11937
Abstract
Postural orthostatic tachycardia syndrome (POTS) is a common accompaniment of a variety of chronic, inflammatory diseases, including long COVID, as are small, insoluble, ‘fibrinaloid’ microclots. We here develop the argument, with accompanying evidence, that fibrinaloid microclots, through their ability to block the flow [...] Read more.
Postural orthostatic tachycardia syndrome (POTS) is a common accompaniment of a variety of chronic, inflammatory diseases, including long COVID, as are small, insoluble, ‘fibrinaloid’ microclots. We here develop the argument, with accompanying evidence, that fibrinaloid microclots, through their ability to block the flow of blood through microcapillaries and thus cause tissue hypoxia, are not simply correlated with but in fact, by preceding it, may be a chief intermediary cause of POTS, in which tachycardia is simply the body’s exaggerated ‘physiological’ response to hypoxia. Similar reasoning accounts for the symptoms bundled under the term ‘fatigue’. Amyloids are known to be membrane disruptors, and when their targets are nerve membranes, this can explain neurotoxicity and hence the autonomic nervous system dysfunction that contributes to POTS. Taken together as a system view, we indicate that fibrinaloid microclots can serve to link POTS and fatigue in long COVID in a manner that is at once both mechanistic and explanatory. This has clear implications for the treatment of such diseases. Full article
(This article belongs to the Special Issue New Challenges and Perspectives in Neurology and Autonomic Disorders)
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16 pages, 4079 KiB  
Perspective
Linking the Extended Autonomic System with the Homeostat Theory: New Perspectives about Dysautonomias
by David S. Goldstein
J. Pers. Med. 2024, 14(1), 123; https://doi.org/10.3390/jpm14010123 - 22 Jan 2024
Cited by 1 | Viewed by 2040
Abstract
Dysautonomias are conditions in which altered functions of one or more components of the autonomic nervous system (ANS) adversely affect health. This essay is about how elucidating mechanisms of dysautonomias may rationalize personalized treatments. Emphasized here are two relatively new ideas—the “extended” autonomic [...] Read more.
Dysautonomias are conditions in which altered functions of one or more components of the autonomic nervous system (ANS) adversely affect health. This essay is about how elucidating mechanisms of dysautonomias may rationalize personalized treatments. Emphasized here are two relatively new ideas—the “extended” autonomic system (EAS) and the “homeostat” theory as applied to the pathophysiology and potential treatments of dysautonomias. The recently promulgated concept of the EAS updates Langley’s ANS to include neuroendocrine, immune/inflammatory, and central components. The homeostat theory builds on Cannon’s theory of homeostasis by proposing the existence of comparators (e.g., a thermostat, glucostat, carbistat, barostat) that receive information about regulated variables (e.g., core temperature, blood glucose, blood gases, delivery of blood to the brain). Homeostats sense discrepancies between the information and response algorithms. The presentation links the EAS with the homeostat theory to understand pathophysiological mechanisms of dysautonomias. Feed-forward anticipatory processes shift input–output curves and maintain plateau levels of regulated variables within different bounds of values—“allostasis”. Sustained allostatic processes increase long-term wear-and-tear on effectors and organs—allostatic load. They decreaseing thresholds for destabilizing and potentially fatal positive feedback loops. The homeostat theory enables mathematical models that define stress, allostasis, and allostatic load. The present discussion applies the EAS and homeostat concepts to specific examples of pediatric, adolescent/adult, and geriatric dysautonomias—familial dysautonomia, chronic orthostatic intolerance, and Lewy body diseases. Computer modeling has the potential to take into account the complexity and dynamics of allostatic processes and may yield testable predictions about individualized treatments and outcomes. Full article
(This article belongs to the Special Issue New Challenges and Perspectives in Neurology and Autonomic Disorders)
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