[Autoimmune Autonomic Ganglionopathy: Solving the 10 Assignments].

Autoimmune autonomic ganglionopathy (AAG) is a rare acquired immune-mediated neurological disease that causes various autonomic symptoms. AAG is induced by autoantibodies for the α3 and ß4 subunits of the ganglionic acetylcholine receptor (gAChR). gAChR antibodies mediate synaptic transmission in all autonomic ganglia, resulting in dysautonomia. Recent clinical and basic research topics in AAG include the following: 1)analysis of clinical features; 2)novel methods for gAChR antibody detection; 3)efficacy of combined immunotherapy; 4)novel experimental AAG; 5)COVID-19 and mRNA COVID-19 vaccination and its association with autonomic dysfunction; and 6)dysautonomia as an immune-related adverse event of immune checkpoint inhibitors in cancer therapy. The author and his collaborators have previously established "10 assignments" to understand the basic research and clinical issues of AAG. In this review, the author describes the current status of research on each of the "10 assignments," incorporating research trends over the last five years.

Cardiorespiratory dysautonomia in post-COVID-19 condition: Manifestations, mechanisms and management.

A significant proportion of COVID-19 patients experience debilitating symptoms for months after the acute infection. According to recent estimates, approximately 1 out of 10 COVID-19 convalescents reports persistent health issues more than 3 months after initial recovery. This 'post-COVID-19 condition' may include a large variety of symptoms from almost all domains and organs, and for some patients it may mean prolonged sick-leave, homestay and strongly limited activities of daily life. In this narrative review, we focus on the symptoms and signs of post-COVID-19 condition in adults - particularly those associated with cardiovascular and respiratory systems, such as postural orthostatic tachycardia syndrome or airway disorders - and explore the evidence for chronic autonomic dysfunction as a potential underlying mechanism. The most plausible hypotheses regarding cellular and molecular mechanisms behind the wide spectrum of observed symptoms - such as lingering viruses, persistent inflammation, impairment in oxygen sensing systems and circulating antibodies directed to blood pressure regulatory components - are discussed. In addition, an overview of currently available pharmacological and non-pharmacological treatment options is presented.

Dysautonomia: Diagnosis and Management.

Dysautonomias are a heterogenous group of disorders that can cause variable symptoms ranging from isolated impairment of one autonomic function to multisystem failure. The causes are also diverse and can be central or peripheral and primary (owing to an intrinsic neurologic cause) or secondary (owing to a disorder that secondarily causes damage to the autonomic nervous system). This review covers common phenotypes of dysautonomias, primary and secondary causes, initial clinical workups, interpretation of common autonomic tests, and first-line treatments. A brief review of autonomic impairment associated with acute and long-COVID is also presented.

Hypoglycemia and Dysautonomia After Bariatric Surgery: a Systematic Review and Perspective.

INTRODUCTION: With the increasing performance of bariatric surgery, rare complications are becoming prevalent. We review the diagnosis and treatment of dysautonomia after bariatric surgery and the limited treatment options available. We summarize the suggested mechanisms and explain why a complete understanding of the etiology has yet to be determined. METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review was performed. RESULTS: Of 448 studies identified in the literature search, 4 studies were reviewed, describing 87 patients diagnosed with dysautonomia. We present a patient who developed severe dysautonomia following conversion of sleeve gastrectomy to gastric bypass. CONCLUSION: Treatment needs to focus on optimizing nutrition, avoiding hypoglycemia, and optimizing volume status.

Transcutaneous vagus nerve stimulation (tVNS) as a potential therapeutic application for neurodegenerative disorders - A focus on dysautonomia in Parkinson's disease.

The understandings of pathogenic processes in major neurodegenerative diseases has significantly advanced in recent years, with evidence showing pathological spread of intraneuronal proteinaceous inclusions as a fundamental factor. In Parkinson's disease (PD), the culprit protein has been identified as α-synuclein as the main component for mediating progressive neurodegeneration. With severe pathology evident in the autonomic nervous system prior to clinical manifestations of PD, pathogenic spread can occur from the peripheral nervous system through key nuclei, such as the anterior olfactory nucleus and dorsal motor nucleus of the glossopharyngeal and vagal nerves, gradually reaching the brainstem, midbrain and cerebral cortex. With this understanding and the proposed involvement of the vagus nerve in disease progression in PD, notably occurring prior to characterized clinical motor features, it raises intriguing questions as to whether vagal nerve pathology can be accurately detected, and importantly used as a reliable marker for determining early neurodegeneration. Along with this is the potential use of vagus nerve neuromodulation for treatment of early disease symptoms like dysautonomia, for modulating sympatho-vagal imbalances and easing severe comorbidities of the disease. In this article, we take a closer look at the pathogenic transmission processes in neurodegenerative disorders that impact the vagus nerve, and how vagus nerve neuromodulation can be potentially applied as a therapeutic approach for major neurodegenerative disorders.

Autoimmune gastrointestinal dysmotility: the interface between clinical immunology and neurogastroenterology.

Autoimmune gastrointestinal dysmotility (AGID), an idiopathic or paraneoplastic phenomenon, is a clinical form of limited autoimmune dysautonomia. The symptoms of AGID and gastrointestinal manifestations in patients with autoimmune rheumatic diseases are overlapping. Antineuronal autoantibodies are often detected in patients with AGID. Autoantibodies play a key role in GI dysmotility; however, whether they cause neuronal destruction is unknown. Hence, the connection between the presence of these autoantibodies and the specific interference in synaptic transmission in the plexus ganglia of the enteric nervous system has to be determined. The treatment options for AGID are not well-defined. However, theoretically, immunomodulatory therapies have been shown to be effective and are therefore used as the first line of treatment. Nonetheless, diverse combined immunomodulatory therapies should be considered for intractable cases of AGID. We recommend comprehensive autoimmune evaluation and cancer screening for clinical diagnosis of AGID. Univocal diagnostic criteria, treatment protocols, and outcome definitions for AGID are required for prompt diagnosis and treatment and appropriate management of immunotherapy, which will circumvent the need for surgeries and improve patient outcome. In conclusion, AGID, a disease at the interface of clinical immunology and neurogastroenterology, requires further investigations and warrants cooperation among specialists, especially clinical immunologists, gastroenterologists, and neurologists.

Anesthesia for Stüve-Wiedemann syndrome: a rare adult patient case report.

Stüve-Wiedemann syndrome (SWS) is a rare genetic disorder characterized by skeletal dysplasia and severe dysautonomia, evidencing a difficult airway approach and likely increased malignant hyperthermia susceptibility. Developmental dysmorphism classically worsens with age, therefore translating in a poor prognosis. In this article, we describe a case of a 27-year-old woman diagnosed with SWS proposed for abscess drainage under dissociative anesthesia. This patient has outlived the life expectancy described for SWS, acknowledging the importance of reporting this rare adult clinical case in what SWS anesthetic management is concerned.

Dysautonomia in 53 cats and dogs: retrospective review of clinical data and outcome.

BACKGROUND: Dysautonomia is a disease characterised by degeneration of autonomic neurons. METHODS: The aim of this study was to perform a retrospective multicentre review of clinical data relating to cats and dogs diagnosed with dysautonomia and to evaluate their outcome. RESULTS: Cats (n=34) and dogs (n=19) with clinical signs consistent with dysautonomia were considered for this retrospective study. Reported clinical findings included oesophageal and gastrointestinal dysmotility and distension, urinary retention, reduced or absent tear production, third eyelid protrusion and inappropriate mydriasis. Treatment was supportive and included gastrointestinal prokinetics, feeding tube placement (oesophageal and percutaneous endoscopic gastrostomy tubes) and medications to treat urinary retention. The survival to discharge was 29 per cent in cats and 47 per cent in dogs. The overall survival in cats was 21 per cent and that in dogs was 32 per cent. Survival of greater than 2 years was seen in six cats and in three dogs. CONCLUSION: This paper illustrates that some animals are able to survive this disease and can have a good long-term prognosis, which is an infrequently reported finding for this disease.

Complex syndromes of chronic pain, fatigue and cognitive impairment linked to autoimmune dysautonomia and small fiber neuropathy.

Chronic fatigue syndrome, postural orthostatic tachycardia syndrome, complex regional pain syndrome and silicone implant incompatibility syndrome are a subject of debate among clinicians and researchers. Both the pathogenesis and treatment of these disorders require further study. In this paper we summarize the evidence regarding the role of autoimmunity in these four syndromes with respect to immunogenetics, autoimmune co-morbidities, alteration in immune cell subsets, production of autoantibodies and presentation in animal models. These syndromes could be incorporated in a new concept of autoimmune neurosensory dysautonomia with the common denominators of autoantibodies against G-protein coupled receptors and small fiber neuropathy. Sjogren's syndrome, which is a classical autoimmune disease, could serve as a disease model, illustrating the concept. Development of this concept aims to identify an apparently autoimmune subgroup of the disputable disorders, addressed in the review, which may most benefit from the immunotherapy.

Disautonomías neurovegetativas: un caso clínico interesante / Neurovegetative dysautonomies: an interesting clinical case

Fundamento: la hiperactividad simpática paroxística consiste en episodios autolimitados de hipertensión arterial, taquicardia, taquipnea, hiperhidrosis, disminución del nivel de conciencia, aumento del tono muscular con postura en extensión, hipertermia, sialorrea y midriasis. Con frecuencia se retrasa su reconocimiento lo que incrementa la morbilidad y mortalidad. Objetivo: conocer la importancia de un diagnóstico y tratamiento precoz de la enfermedad para mayor supervivencia del paciente afectado. Presentación del caso: paciente de 33 años de edad, femenina, que desarrolló una hiperactividad simpática paroxística asociada con hidrocefalia obstructiva. Conclusiones: debe sospecharse la enfermedad en pacientes con daño cerebral agudo de diversas causas. El diagnóstico temprano es vital para evitar estudios diagnósticos e intervenciones innecesarias e iniciar un tratamiento rápido y apropiado que modifique la evolución del síndrome(AU)

Background: paroxysmal sympathetic hyperactivity consists of self-limited episodes of arterial hypertension, tachycardia, tachypnea, hyperhidrosis, decreased level of consciousness, increased muscle tone with extension posture, hyperthermia, sialorrhea and mydriasis. Frequently their recognition is delayed, which increases morbidity and mortality. Objective: to make known the importance of an early diagnosis and treatment of the entity for greater survival of the affected patient. Case report: a 33-years-old female patient who developed a paroxysmal sympathetic hyperactivity associated with obstructive hydrocephalus. Conclusions: the entity should be suspected in patients with acute brain damage of various etiologies. Early diagnosis is vital to avoid unnecessary diagnostic studies and interventions and to initiate a rapid and appropriate treatment that modifies the evolution of the syndrome(AU)

Calming the Storm: Dysautonomia for the Pediatrician.

Dysautonomia is a potentially life-threatening syndrome seen in many different types of brain injuries. It involves paroxysmal sympathetic hyperactivity and typically includes a constellation of symptoms, including: tachycardia, tachypnea, hyperthermia, hypertension, diaphoresis, hypertonia, and/or decerebrate or decorticate posturing. It is a clinical diagnosis of exclusion. A multimodal treatment approach is necessary including environmental modifications along with pharmacotherapy. Early management can help prevent comorbidities including secondary brain injury while also improving patient outcomes. This discussion serves as an overview of dysautonomia with a focus on management in the pediatric population including an example of a clinical algorithm and a review of the commonly used medications.

Short-Term Efficacy of CBD-Enriched Hemp Oil in Girls with Dysautonomic Syndrome after Human Papillomavirus Vaccination.

BACKGROUND: Cannabidiol (CBD)-based treatments for several diseases, including Tourette's syndrome, multiple sclerosis, epilepsy, movement disorders and glaucoma, are proving to be beneficial and the scientific clinical background of the drug is continuously evolving. OBJECTIVES: To investigate the short-term effect of CBD-enriched hemp oil for relieving symptoms and improving the life quality (QOL) in young girls with adverse drug effects (ADRs) following human papillomavirus (HPV) vaccine. METHODS: In this anecdotal, retrospective, "compassionate-use", observational, open-label study, 12 females (age 12-24 years) with severe somatoform and dysautonomic syndrome following HPV vaccination were given sublingual CBD-rich hemp oil drops, 25 mg/kg per day supplemented by 2-5 mg/ml CBD once a week until a maximum dose of 150 mg/ml CBD per day was reached over a 3 month period. Patients' quality of life was evaluated using the medical outcome short-form health survey questionnaire (SF-36). RESULTS: Two patients dropped out due to iatrogenic adverse events and another two patients stopped the treatment early due to lack of any improvement. SF-36 showed significant benefits in the physical component score (P < 0.02), vitality (P < 0.03) and social role functioning (P < 0.02) after the treatment. The administration of hemp oil also significantly reduced body pain according to the SF-36 assessment. No significant differences from the start of treatment to several months post-treatment were detected in role limitations due to emotional reactions (P = 0.02). CONCLUSIONS: This study demonstrated the safety and tolerability of CBD-rich hemp oil and the primary efficacy endpoint. Randomized controlled trials are warranted to characterize the safety profile and efficacy of this compound.

Exercise and the multidisciplinary holistic approach to adolescent dysautonomia.

AIM: To determine whether an eight-week strength training programme as part of a multidisciplinary approach would minimise symptoms and improve quality of life in patients with dysautonomia. METHODS: Adolescents referred to a tertiary-level cardiology service from May 2014-December 2015 with symptoms of dysautonomia were eligible. Participants completed an exercise test and a quality of life (QoL) questionnaire (PedsQL) prior to the intervention. Participants were asked to complete exercises five times per week. After eight weeks, participants returned for follow-up testing. Parents completed a proxy report of their child's QoL at both time points. RESULTS: A total of 17 participants completed the study protocol with an adherence rate of up to 50%. Post-intervention, QoL scores improved across all levels in the participants [total 65.2 (50.4-74.7) vs 48.9 (37.5-63.0); p = 0.006; psychosocial 65.8 (56.1-74.6) vs 50.0 (41.7-65.8); p = 0.010; physical 62.5 (37.5-76.6) vs 43.8 (25-68.5); p = 0.007] and their parent proxy reports [total 63.5 (48.7-81.3) vs 50.0 (39.3-63.0); p = 0.004; psychosocial 62.1 (52.1-81.3) vs 50.0 (39.6-59.2); p = 0.001; physical 62.5 (51.6-80.0) vs 50.0 (27.5-70.3); p = 0.003]. Treadmill time also improved (9.1 vs 8.0 minutes; p = 0.005). CONCLUSION: Following an eight-week strength training programme, dysautonomia patients report a significant improvement in both their quality of life and endurance time.

Noninvasive ventilation for neuromuscular respiratory failure: when to use and when to avoid.

PURPOSE OF REVIEW: Neuromuscular respiratory failure can occur from a variety of diseases, both acute and chronic with acute exacerbation. There is often a misunderstanding about how the nature of the neuromuscular disease should affect the decision on how to ventilate the patient. This review provides an update on the value and relative contraindications for the use of noninvasive ventilation in patients with various causes of primary neuromuscular respiratory failure. RECENT FINDINGS: Myasthenic crisis represents the paradigmatic example of the neuromuscular condition that can be best treated with noninvasive ventilation. Timely use of noninvasive ventilation can substantially reduce the duration of ventilatory assistance in these patients. Noninvasive ventilation can also be very helpful after extubation in patients recovering from an acute cause of neuromuscular respiratory failure who have persistent weakness. Noninvasive ventilation can improve quality of survival in patients with advanced motor neuron disorder (such as amyotrophic lateral sclerosis) and muscular dystrophies, and can avoid intubation when these patients present to the hospital with acute respiratory failure. Attempting noninvasive ventilation is not only typically unsuccessful in patients with Guillain-Barre syndrome, but can also be dangerous in these cases. SUMMARY: Noninvasive ventilation can be very effective to treat acute respiratory failure caused by myasthenia gravis and to prevent reintubation in other neuromuscular patients, but should be used cautiously for other indications, particularly Guillain-Barre syndrome.

Complex regional pain syndrome and dysautonomia in a 14-year-old girl responsive to therapeutic plasma exchange.

Reflex sympathetic dystrophy, also known as complex regional pain syndrome (CRPS), has recently been shown to be associated with autoantibodies against ß2-adrenergic and muscarinic M2 receptors. In addition to pain and sudomotor/vasomotor symptoms, dysautonomia is also observed in a subset of CRPS patients. Despite its severity, there are few effective therapies for CRPS described to date. We report a case of a 14-year-old girl with CRPS of her right leg and dysautonomia (gastroparesis, postural tachycardia) refractory to multiple therapies, successfully treated with therapeutic plasma exchange (TPE) with albumin replacement. The patient, who has serum anti ß2-adrenergic and muscarinic M2 receptor autoantibodies in addition to nicotinic acetylcholine receptor ganglionic autoantibodies, underwent an initial course of five TPEs over a 2-week period. She demonstrated a clinical response to TPE as manifested by a rapid improvement in her fatigue and gastroparesis, with a gradual yet significant improvement in her leg pain and sudomotor/vasomotor flares. Following the loading procedures, the patient was treated with rituximab. She continues to require periodic TPE to maintain a remission, with additional immunosuppression being considered long term. Although further studies are needed, TPE (in combination with immunosuppression) may be an appropriate therapy for CRPS patients with detectable autoantibodies, as it is for better characterized diseases with autoantibodies against neuronal surface receptors such as myasthenia gravis or Lambert Eaton myasthenic syndrome. J. Clin. Apheresis 31:368-374, 2016. © 2015 Wiley Periodicals, Inc.

Vertigo with dysautonomia and serious allergy: An unusual case of juvenile Ménière's disease.

A 13-year-old boy with frequent episodes of vertigo and otologic symptoms was diagnosed with Ménière's disease (MD) but failed to respond to conventional treatment. Allergy testing revealed serious reactions to many allergens, and autonomic tests showed he was dysautonomic. An allergen-restricted diet and treatment of dysautonomia were effective, the boy being free from vertigo within 2 months. This case provides evidence to promote the understanding of MD in children. The authors hypothesize that the autonomic nerves and the immune system can interact, and that such an interaction of dysautonomia and allergy can lead to a serious vertigo episode.

Headache and Pain in Guillain-Barré Syndrome.

While moderate and severe back or extremity pain is frequent in Guillain-Barré syndrome (GBS), headache appears to be uncommon. Most of the reports of headache in GBS place it in the context of the posterior reversible encephalopathy syndrome (PRES) which is increasingly recognized as a likely dysautonomia-related GBS complication. There are also a few reports of headache in the setting of increased CSF pressure and papilledema and in association with the Miller Fisher GBS variant. In comparison, back and extremity pain is highly prevalent. Aching muscle pain and neuropathic pain are the two most common of several pain types. Pain may be a heralding feature and has been described in patients as long as 2 years after disease onset. Pain management is a major axis of treatment in GBS. Gabapentin is a reasonable first-line choice, and opioid medications can be added for more severe pain but there are few clinical trials to inform specific recommendations. While the understanding of pain pathophysiology in GBS is incomplete, its prevalence and clinical impact are increasingly recognized and studied. Pain should be considered a cardinal manifestation of GBS along with acute, mostly symmetric weakness and diminished reflexes.