Early in the pandemic, clinicians recognized an overlap between Long COVID symptoms and dysautonomia, suggesting autonomic nervous system (ANS) dysfunction. Our clinical experience at Johns Hopkins with primary dysautonomia suggested heritability of sympathetic dysfunction, manifesting primarily as hyperhidrosis and as other dysautonomia symptoms. Whole exome sequencing revealed mutations in genes regulating electrical signaling in the nervous system, thus providing a genetic basis for the sympathetic overdrive observed. We hypothesize that dysautonomia in Long COVID requires two molecular hits: a genetic vulnerability to prime the ANS and a SARS-CoV-2 infection, as an immune trigger, to further disrupt ANS function resulting in increased sympathetic activity. Indeed, Long COVID patients show signs of chronic inflammation and autoimmunity. We have translated this two-hit concept to the clinic using ion channel inhibitors to target genetic susceptibility and immunomodulators to treat inflammation. This multi-hit hypothesis shows promise for managing Long COVID and merits further study.

BACKGROUND: After COVID-19 infection, 10-20% of patients suffer from varying symptoms lasting more than 12 weeks (Long COVID, LC). Exercise intolerance and fatigue are common in LC. The aim was to measure the maximal exercise capacity of the LC patients with these symptoms and to analyze whether this capacity was related to heart rate (HR) responses at rest and during exercise and recovery, to find out possible sympathetic overactivity, dysautonomia or chronotropic incompetence.
METHODS: Cardiopulmonary exercise test was conducted on 101 LC patients, who were admitted to exercise testing. The majority of them (86%) had been treated at home during their acute COVID-19 infection. Peak oxygen uptake (VO2peak), maximal power during the last 4 min of exercise (Wlast4), HRs, and other exercise test variables were compared between those with or without subjective exercise intolerance, fatigue, or both.
RESULTS: The measurements were performed in mean 12.7 months (SD 5.75) after COVID-19 infection in patients with exercise intolerance (group EI, 19 patients), fatigue (group F, 31 patients), their combination (group EI + F, 37 patients), or neither (group N, 14 patients). Exercise capacity was, in the mean, normal in all symptom groups and did not significantly differ among them. HRs were higher in group EI + F than in group N at maximum exercise (169/min vs. 158/min, p = 0.034) and 10 min after exercise (104/min vs. 87/min, p = 0.028). Independent of symptoms, 12 patients filled the criteria of dysautonomia associated with slightly decreased Wlast4 (73% vs. 91% of sex, age, height, and weight-based reference values p = 0.017) and 13 filled the criteria of chronotropic incompetence with the lowest Wlast4 (63% vs. 93%, p < 0.001), VO2peak (70% vs. 94%, p < 0.001), the lowest increase of systolic blood pressure (50 mmHg vs. 67 mmHg, p = 0.001), and the greatest prevalence of slight ECG-findings (p = 0.017) compared to patients without these features. The highest prevalence of chronotropic incompetence was seen in the group N (p = 0.022).
CONCLUSIONS: This study on LC patients with different symptoms showed that cardiopulmonary exercise capacity was in mean normal, with increased sympathetic activity in most patients. However, we identified subgroups with dysautonomia or chronotropic incompetence with a lowered exercise capacity as measured by Wlast4 or VO2peak. Subjective exercise intolerance and fatigue poorly foresaw the level of exercise capacity. The results could be used to plan the rehabilitation from LC and for selection of the patients suitable for it.

OBJECTIVE: Olfactory dysfunction or dysautonomia is one of the earliest prodromal nonmotor symptoms of Parkinson\'s disease (PD). We aimed to investigate whether PD patients with dysautonomia and hyposmia at the de novo stage present different prognoses regarding PD dementia (PDD) conversion, motor complication development, and change in levodopa-equivalent doses (LED).
METHODS: In this retrograde cohort study, we included 105 patients with newly diagnosed PD patients who underwent cross-cultural smell identification test (CC-SIT), autonomic function tests (AFT), and dopamine transporter (DAT) scan at the de novo stage. PD patients were divided into Hyposmia + /Dysautonomia + (H + /D +) and Hyposmia - /Dysautonomia - (H - /D -) groups depending on the result of AFT and CC-SIT. Baseline clinical, cognitive, imaging characteristics, longitudinal risks of PDD development and motor complication occurrence, and longitudinal LED changes were compared between the two groups.
RESULTS: When compared with the H - /D - group, the H + /D + group showed lower standardized uptake value ratios in all subregions, lower asymmetry index, and steeper ventral - dorsal gradient in the DAT scan. The H + /D + group exhibited poorer performance in frontal/executive function and a higher risk of PDD development. The risk of motor complications including levodopa-induced dyskinesia, wearing off, and freezing of gait, was comparable between the two groups. The analysis of longitudinal changes in LED using a linear mixed model showed that the increase of LED in the H + /D + group was more rapid.
CONCLUSIONS: Our results suggest that PD patients with dysautonomia and hyposmia at the de novo stage show a higher risk of PD dementia conversion and rapid progression of motor symptoms.

OBJECTIVE: Coronavirus disease (COVID-19) is a respiratory disease caused by SARS-CoV-2, which complicates the functioning of multiple systems, including the autonomic nervous system (ANS), causing dysautonomia. Investigation of dysautonomia and its association with exposure to COVID-19 is limited in healthy people. Therefore, the study aimed to investigate the relationship between ANS dysautonomia and coronavirus exposure and compare the ANS function between exposed and non-exposed to COVID-19.
METHODS: The study involved 141 participants, with a mean age of 18-24.5 years, 83% male (49.6% exposed to COVID-19). The ANS was measured using a composite autonomic symptom scale (COMPASS-31) questionnaire and heart rate variability (HRV) using photoplethysmography. Exposure to COVID-19 was investigated using two national health-status tracking and COVID-19 exposure applications, \"Sehhaty\" and \"Twakkalna\".
RESULTS: A significantly inverse weak correlation between COMPASS-31 scores and COVID-19 exposure (r=-0.2, p=0.04). No significant association was found between HRV and COVID-19 exposure. COMPASS-31 scores for the exposed group (median=15, n=70) were significantly higher than those for the non-exposed group (median=12, n=71), U=1,913.5, p=0.03. Height (r=-0.4, p=0.002) and gender (r=0.3, p=0.001) were moderately correlated with COMPASS-31 among the exposed group.
CONCLUSIONS: These findings indicated that exposure to COVID-19 was associated with poorer ANS scores measured via COMPASS-31. Additionally, exposure to COVID-19 resulted in higher dysautonomia symptoms than non-exposed. Height and gender differences contribute to the severity of dysautonomia among exposed people.

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Allergist-immunologists face significant challenges as experts in an ever-evolving field of neuroimmunology. Among these challenges is the increasingly frequent need to counsel patients with suspected mast cell activation disorders about perceived comorbidities, which may include hypermobile Ehlers-Danlos syndrome, amplified pain syndrome, fibromyalgia, burning sensation syndromes, migraines, irritable bowel syndrome, and postural orthostatic tachycardia syndrome. Patients may experience comorbid anxiety, panic disorder, and depression associated with disturbed sleep, fatigue, and cognitive impairment that often worsen when their physical symptoms increase in severity. These conditions may mimic mast cell activation disorders and are emotionally taxing for patients and clinicians because they are often accompanied by vague diagnostic courses, perceived unmanageability, social stigma, and significant impairment in quality of life. Combined with relatively poorly researched therapies, it is no surprise that clinicians may feel overwhelmed or find it difficult to provide consistently compassionate care for this population. In this article, we review available therapies for these conditions, which run the gamut from physical therapy to antidepressants to multimodal pain control. We highlight the benefit of multidisciplinary care within the primary care home, which includes an important role by the allergist-immunologist. By outlining simple approaches to initial treatment, we hope to empower clinicians with the tools needed to curb emotional burnout and embrace this patient population with compassion.

OBJECTIVE: Dysautonomia has been associated with paraneoplastic neurological syndrome (PNS)-related mortality in anti-Hu PNS, but its frequency and spectrum remain ill-defined. We describe anti-Hu patients with dysautonomia, estimate its frequency, and compare them to patients without dysautonomia.
METHODS: Patients with anti-Hu antibodies diagnosed in the study centre (1990-2022) were retrospectively reviewed; those with autonomic signs and symptoms were identified.
RESULTS: Among 477 anti-Hu patients, 126 (26%) had dysautonomia (the only PNS manifestation in 7/126, 6%); gastrointestinal (82/126, 65%), cardiovascular (64/126, 51%), urogenital (24/126, 19%), pupillomotor/secretomotor (each, 11/126, 9%), and central hypoventilation (10/126, 8%). Patients with isolated CNS involvement less frequently had gastrointestinal dysautonomia than those with peripheral (alone or combined with CNS) involvement (7/23, 30% vs. 31/44, 70% vs. 37/52, 71%; P = 0.002); while more frequently central hypoventilation (7/23, 30% vs. 1/44, 2.3% vs. 2/52, 4%; P < 0.001) and/or cardiovascular alterations (18/23, 78% vs. 20/44, 45% vs. 26/52, 50%; P = 0.055). Median [95% CI] overall survival was not significantly different between patients with (37 [17; 91] months) or without dysautonomia (28 [22; 39] months; P = 0.78). Cardiovascular dysautonomia (HR: 1.57, 95% CI [1.05; 2.36]; P = 0.030) and central hypoventilation (HR: 3.51, 95% CI [1.54; 8.01]; P = 0.003) were associated with a higher risk of death, and secretomotor dysautonomia a lower risk (HR: 0.28, 95% CI [0.09; 0.89]; P = 0.032). Patients with cardiovascular dysautonomia dying ≤ 1 year from clinical onset had severe CNS (21/27, 78%), frequently brainstem (13/27, 48%), involvement.
CONCLUSIONS: Anti-Hu PNS dysautonomia is rarely isolated, frequently gastrointestinal, cardiovascular and urogenital. CNS dysfunction, particularly brainstem, associates with lethal cardiovascular alterations and central hypoventilation, while peripheral involvement preferentially associates with gastrointestinal or secretomotor dysautonomia, being the latest more indolent.

Maintaining cerebral perfusion in the early stages of recovery after stroke is paramount. Autoregulatory function may be impaired during this period leaving cerebral perfusion directly reliant on intravascular volume and blood pressure (BP) with increased risk for expanding cerebral infarction during periods of low BP and hemorrhagic transformation during BP elevations. We suspected that dysautonomia is common during the acute period related to both pre-existing vascular risk factors and potentially independent of such conditions. Thus, we sought to understand the state of the science specific to dysautonomia and acute stroke. The scoping review search included multiple databases and key terms related to acute stroke and dysautonomia. The team employed a rigorous review process to identify, evaluate, and summarize relevant literature. We additionally summarized common clinical approaches used to detect dysautonomia at the bedside. The purpose of this scoping review is to understand the state of the science for the identification, treatment, and impact of dysautonomia on acute stroke patient outcomes. There is a high prevalence of dysautonomia among persons with stroke, though there is significant variability in the type of measures and definitions used to diagnose dysautonomia. While dysautonomia appears to be associated with poor functional outcome and post-stroke complications, there is a paucity of high-quality evidence, and generalizability is limited by heterogenous approaches to these studies. There is a need to establish common definitions, standard measurement tools, and a roadmap for incorporating these measures into clinical practice so that larger studies can be conducted.