Tag: dysautonomia

A Clinical Qualification Protocol Highlights Overlapping Genomic Influences and Neuro-Autonomic Mechanisms in Ehlers-Danlos and Long COVID-19 Syndromes

Abstract:

A substantial fraction of the 15% with double-jointedness or hypermobility have the traditionally ascertained joint-skeletal, cutaneous, and cardiovascular symptoms of connective tissue dysplasia and its particular manifestation as Ehlers-Danlos syndrome (EDS). The holistic ascertainment of 120 findings in 1261 EDS patients added neuro-autonomic symptoms like headaches, muscle weakness, brain fog, chronic fatigue, dyspnea, and bowel irregularity to those of arthralgia and skin laxity, 15 of these symptoms shared with those of post-infectious SARS-CoV-2 (long COVID-19).

Underlying articulo-autonomic mechanisms guided a clinical qualification protocol that qualified DNA variants in 317 genes as having diagnostic utility for EDS, six of them identical (F2-LIFR-NLRP3-STAT1-T1CAM1-TNFRSF13B) and eighteen similar to those modifying COVID-19 severity/EDS, including ADAMTS13/ADAMTS2-C3/C1R-IKBKG/IKBKAP-PIK3C3/PIK3R1-POLD4/POLG-TMPRSS2/TMPRSS6-WNT3/WNT10A.

Also, contributing to EDS and COVID-19 severity were forty and three genes, respectively, impacting mitochondrial functions as well as parts of an overlapping gene network, or entome, that are hypothesized to mediate the cognitive-behavioral, neuro-autonomic, and immune-inflammatory alterations of connective tissue in these conditions. The further characterization of long COVID-19 natural history and genetic predisposition will be necessary before these parallels to EDS can be carefully delineated and translated into therapies.

Source: Wilson GN. A Clinical Qualification Protocol Highlights Overlapping Genomic Influences and Neuro-Autonomic Mechanisms in Ehlers-Danlos and Long COVID-19 Syndromes. Curr Issues Mol Biol. 2023 Jul 17;45(7):6003-6023. doi: 10.3390/cimb45070379. PMID: 37504295; PMCID: PMC10378515. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10378515/ (Full text)

Vagus nerve inflammation contributes to dysautonomia in COVID-19

Abstract:

Dysautonomia has substantially impacted acute COVID-19 severity as well as symptom burden after recovery from COVID-19 (long COVID), yet the underlying causes remain unknown. Here, we hypothesized that vagus nerves are affected in COVID-19 which might contribute to autonomic dysfunction.

We performed a histopathological characterization of postmortem vagus nerves from COVID-19 patients and controls, and detected SARS-CoV-2 RNA together with inflammatory cell infiltration composed primarily of monocytes. Furthermore, we performed RNA sequencing which revealed a strong inflammatory response of neurons, endothelial cells, and Schwann cells which correlated with SARS-CoV-2 RNA load. Lastly, we screened a clinical cohort of 323 patients to detect a clinical phenotype of vagus nerve affection and found a decreased respiratory rate in non-survivors of critical COVID-19.

Our data suggest that SARS-CoV-2 induces vagus nerve inflammation followed by autonomic dysfunction which contributes to critical disease courses and might contribute to dysautonomia observed in long COVID.

Source:Woo MS, Shafiq M, Fitzek A, Dottermusch M, Altmeppen H, Mohammadi B, Mayer C, Bal LC, Raich L, Matschke J, Krasemann S, Pfefferle S, Brehm TT, Lütgehetmann M, Schädler J, Addo MM, Schulze Zur Wiesch J, Ondruschka B, Friese MA, Glatzel M. Vagus nerve inflammation contributes to dysautonomia in COVID-19. Acta Neuropathol. 2023 Jul 15. doi: 10.1007/s00401-023-02612-x. Epub ahead of print. PMID: 37452829. https://link.springer.com/article/10.1007/s00401-023-02612-x (Full text)

Persistent post-COVID-19 neuromuscular symptoms

Abstract:

Neuromuscular symptoms may develop or persist after resolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Besides residual sensorimotor symptoms associated with acute neuromuscular complications of coronavirus disease-2019 (COVID-19), such as Guillain-Barré syndrome, critical illness neuromyopathy, and rhabdomyolysis, patients may report persistent autonomic symptoms, sensory symptoms, and muscle symptoms in the absence of these acute complications, including palpitations, orthostatic dizziness and intolerance, paresthesia, myalgia, and fatigue.

These symptoms may be associated with long COVID, also known as post-COVID-19 conditions or postacute sequelae of SARS-CoV-2 infection, which may significantly impact quality of life. Managing these symptoms represents a challenge for health-care providers.

Recent advances have identified small-fiber neuropathy as a potential etiology that may underlie autonomic dysfunction and paresthesia in some long COVID patients. The pathogenic mechanisms underlying myalgia and fatigue remain elusive and need to be investigated. Herein we review the current state of knowledge regarding the evaluation and management of patients with persistent post-COVID-19 neuromuscular symptoms.

Source: Abrams RMC, Zhou L, Shin SC. Persistent post-COVID-19 neuromuscular symptoms. Muscle Nerve. 2023 Jul 19. doi: 10.1002/mus.27940. Epub ahead of print. PMID: 37466117. https://onlinelibrary.wiley.com/doi/10.1002/mus.27940 (Full text)

Evaluation of Outpatients in the Post-COVID-19 Period in Terms of Autonomic Dysfunction and Silent Ischemia

Abstract:

Introduction and objective: In this context, the objective of this study is to evaluate the 24-hour ambulatory electrocardiography (ECG) recordings, autonomous function with heart rate variability (HRV), and silent ischemia (SI) attacks with ST depression burden (SDB) and ST depression time (SDT) of post-COVID-19 patients. Materials and methods: The 24-hour ambulatory ECG recordings obtained >12 weeks after the diagnosis of COVID-19 were compared between 55 consecutive asymptomatic and 73 symptomatic post-COVID-19 patients who applied to the cardiology outpatient clinic with complaints of palpitation and chest pain in comparison with asymptomatic post-COVID-19 patients in Kars Harakani state hospital. SDB, SDT, and HRV parameters were analyzed. Patients who had been on medication that might affect HRV, had comorbidities that might have caused coronary ischemia, and were hospitalized with severe COVID-19 were excluded from the study.

Results: There was no significant difference between symptomatic and asymptomatic post-COVID-19 patients in autonomic function. On the other hand, SDB and SDT parameters were significantly higher in symptomatic post-COVID-19 patients than in asymptomatic post-COVID-19 patients. Multivariate analysis indicated that creatine kinase-myoglobin binding (CK-MB) (OR:1.382, 95% CI:1.043-1.831; p=0.024) and HRV index (OR: 1.033, 95% CI:1.005-1.061; p=0.019) were found as independent predictors of palpitation and chest pain symptoms in post-COVID-19 patients.

Conclusion: The findings of this study revealed that parasympathetic overtone and increased HRV were significantly higher in symptomatic patients with a history of COVID-19 compared to asymptomatic patients with a history of COVID-19 in the post-COVID-19 period. Additionally, 24-hour ambulatory ECG recordings and ST depression analysis data indicated that patients who experienced chest pain in the post-COVID-19 period experienced silent ischemia (SI) attacks.

Source: Karakayalı M, Artac I, Ilis D, Omar T, Rencuzogullari I, Karabag Y, Altunova M, Arslan A, Guzel E. Evaluation of Outpatients in the Post-COVID-19 Period in Terms of Autonomic Dysfunction and Silent Ischemia. Cureus. 2023 Jun 11;15(6):e40256. doi: 10.7759/cureus.40256. PMID: 37440812; PMCID: PMC10335598. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10335598/ (Full text)

High incidence of autonomic dysfunction and postural orthostatic tachycardia syndrome in patients with long-COVID: Implications for management and healthcare planning

Abstract:

Background: Autonomic dysfunction including postural orthostatic tachycardia syndrome (POTS) has been reported in individuals with post-acute sequelae of Covid-19 (PASC). However, the degree of dysautonomia in PASC has not been compared to those with POTS and healthy controls.

Methods: All participants were prospectively enrolled between 5th August 2021 and 31st October 2022. Autonomic testing included beat-to-beat hemodynamic monitoring to assess respiratory sinus arrhythmia, Valsalva ratio and orthostatic changes during a 10-minute active standing test as well as Sudomotor assessment. The Composite Autonomic Symptom Score (COMPASS-31) was used to assess symptoms and the Euroquol 5-Dimension survey (EQ-5D-5L) was used to assess health-related quality of life (HrQoL) measures.

Results: A total of 99 participants (n=33 PASC, n=33 POTS and n=33 healthy controls; median age 32 [18], 85.9% females) were included. Compared to healthy controls, the PASC and POTS cohorts demonstrated significantly reduced respiratory sinus arrhythmia (p<0.001), greater heart rate increase during 10-minute active standing test (p<0.001), greater burden of autonomic dysfunction evidenced by higher COMPASS-31 scores across all subdomains (all p<0.001) and poor HrQoL across all EQ-5D-5L domains (all p<0.001), lower median EQ-VAS (p<0.001) and lower utility scores (p<0.001). The majority (79%) of those with PASC met the internationally established criteria for POTS.

Conclusion: The prevalence of autonomic symptomology or POTS was high in those with PASC, leading to poor HrQoL and high health disutility. Autonomic testing should be routinely undertaken in those with PASC to aid diagnosis and direct appropriate management to improve health outcomes.

Trial registration: ANZCTR 12621000476831.

Source: Seeley MC, Gallagher C, Ong E, Langdon A, Chieng J, Bailey D, Page A, Lim HS, Lau DH. High incidence of autonomic dysfunction and postural orthostatic tachycardia syndrome in patients with long-COVID: Implications for management and healthcare planning. Am J Med. 2023 Jun 28:S0002-9343(23)00402-3. doi: 10.1016/j.amjmed.2023.06.010. Epub ahead of print. PMID: 37391116. https://www.amjmed.com/article/S0002-9343(23)00402-3/fulltext (Full text)

Vagus Nerve Dysfunction in the Post-COVID-19 Condition

Abstract:

Background: The post-COVID-19 condition (PCC) is a disabling syndrome affecting 5-15% of subjects who survive COVID-19. SARS-CoV-2 mediated vagus nerve dysfunction could explain some of the PCC symptoms, including persistent dysphonia, dysphagia, dyspnea, dizziness, tachycardia, orthostatic hypotension, gastrointestinal disturbances or neurocognitive complaints.

Methods: We performed a cross-sectional pilot study in subjects with PCC with symptoms suggesting vagus nerve dysfunction (n=30) and compared them to subjects fully recovered from acute COVID-19 (n=14) and individuals never infected with SARS-CoV-2 (n=16), matched by age and sex. We evaluated the structure and function of the vagus nerve, including dysphonia, dysphagia, and dysautonomia tests, and evaluated the structure and function of respiratory muscles with vagus nerve innervation.

Findings: Participants were mostly (80%) women with median 44 years of age. Their most prevalent symptoms were cognitive dysfunction (83%), dyspnea (80%) and tachycardia (80%). Compared with COVID-19-recovered and uninfected controls, respectively, subjects with PCC were more likely to show thickening and hyperechogenic vagus nerve in neck ultrasounds (mean ± SD left vagus nerve cross-sectional area: 2.4 ± 0.97mm2 vs. 2 ± 0.52mm2 vs. 1.9 ± 0.73 mm2, p=0.080), flattened diaphragmatic curve (47% vs 6% vs 14%, p=0.007), reduced esophageal peristalsis (34% vs 0% vs 21%, p=0.020), gastroesophageal reflux (34% vs 19% vs 7%, p=0.130), hiatal hernia (25% vs 0% vs 7%, p=0.050) and reduced maximal inspiratory pressure in functional respiratory tests (62% vs. 6% vs. 17%, p ≤0.001).

Interpretation: Vagus nerve dysfunction has a central pathogenic role in the pathophysiology of the post-COVID condition.

Source: Lladós, Gemma and Massanella, Marta and Coll-Fernández, Roser and Rodríguez, Raúl and Hernández, Electra and Lucente, Giuseppe and López, Cristina and Loste, Cora and Santos, José Ramón and España-Cueto, Sergio and Nevot, Maria and Muñoz-López, Francisco and Arrieta, Sandra Silva and Brander, Christian and Durà, Maria José and Cuadras, Patricia and Bechini, Jordi and Tenesa, Montserrat and Martinez-Piñeiro, Alicia and Herrero, Cristina and Chamorro, Anna and Garcia, Anna and Grau, Eulalia and Clotet, Bonaventura and Paredes, Roger and Mateu, Lourdes and Unit, Germans Trias Long-COVID, Vagus Nerve Dysfunction in the Post-COVID-19 Condition. Available at SSRN: https://ssrn.com/abstract=4479598 or http://dx.doi.org/10.2139/ssrn.4479598

Clinical Features of Post-Covid Syndrome

Abstract:

There is no common understanding of the clinical picture of post-covid syndrome. The US regulator CDC proposes to highlight:

(A) persistent symptoms and conditions that begin during acute COVID-19 illness;

B) new onset late complications after asymptomatic disease or a period of acute symptomatic relief or remission;

(C) the evolution of symptoms and conditions that include some persistent symptoms (eg, shortness of breath) with the addition of new symptoms or conditions over time (eg, cognitive difficulties).

Some manifestations may resemble other postviral syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome, dysautonomia (eg, postural orthostatic tachycardia syndrome), or mast cell activation syndrome.

Source: Sayfulloyevich, P. S. ., & Musayevich, U. R. . (2023). Clinical Features of Post-Covid Syndrome. EUROPEAN JOURNAL OF INNOVATION IN NONFORMAL EDUCATION, 3(6), 34–36. Retrieved from http://inovatus.es/index.php/ejine/article/view/1786 http://inovatus.es/index.php/ejine/article/view/1786/1794 (Full text)

Diagnostic value of 24-h ECG recording in Long COVID patients with postural orthostatic tachycardia syndrome

Abstract:

Background: Cardiovascular autonomic dysfunction (CVAD) is a major complication for a large proportion of Long COVID (LC) patients. The main phenotype of CVAD is postural orthostatic tachycardia syndrome (POTS), commonly observed as a sequalae of COVID infection, thus defining a subset of LC patients. POTS is a cardiovascular autonomic disorder characterized by an excessive heart rate (HR) increase and symptoms of orthostatic intolerance when assuming upright posture, occurring predominantly in young and middle-aged women. Since the start of COVID-19 pandemic it has been observed that up to 30% of patients with post-COVID-19 syndrome develop POTS with such symptoms as tachycardia, orthostatic intolerance, fatigue, and cognitive impairment. The heterogeneity of POTS symptoms makes the diagnosis and appropriate management of POTS more difficult and one of the first steps for clinicians is to develop and test relevant diagnostic methods for POTS.
Methods: Patients with persistent symptoms, 3 months after an acute SARS-CoV-2 infection were referred to the multi-disciplinary LC unit at a hospital in Sweden. Consecutive patients seen at this unit from 2021 to 2022 underwent a 24-h ECG recording. LC patients with POTS verified by active standing test and/or head-up tilt testing were prospectively enrolled in the study database and were compared with LC patients without POTS according to 3 specific analyses based on 24-h ECG recording : (1) cardiac autonomic activity expressed by heart rate variability, HRV (SDNN and RMSSD in ms) parameters, (2) awakening HR increase (HR mean 10 min before vs. 30 min after awakening) and (3) HR spikes (number/h if at least over than 30 bpm and at least during 30 s). Control group consisted of healthy subjects from 24-h ECG recordings database (HRV analysis) of a hospital in France. Data were expressed as mean (± standard deviation, SD) and frequencies (%).
Results: A total of 120 LC patients (mean age: 42.7 +/-9.97 y, 88% women) and 100 healthy subjects (mean age: 46.4 +/-10.2 y, 82% women) were included. LC with POTS (42%) was associated with (1) a decrease in most HRV parameters (mean SDNN: 86.8 +/-24.3 vs. 108.7 +/-24.1 ms, p=0.03), and the most reduced components were those related to the parasympathetic tone (mean RMSSD: 34,5 +/-20.4 vs. 45.6 +/-22.1 ms, p=0.04), (2) an abrupt and sustained increase in HR during the first 30 min after awakening (+30%, p<0.05) and (3) a higher number of HR spikes per h (1.4 +/-0.8 vs. 0.8 +/-0.7/h, p<0.001) compared with healthy subjects (HRV) and LC patients without POTS (awakenings and HR peaks) respectively.
Conclusion: A triple analysis of 24-h ECG recordings revealed presence of autonomic dysfunction in LC patients with POTS compared with those without POTS. This novel analysis may be introduced in the clinic for screening and therapy monitoring.

Source: D Hupin and others, Diagnostic value of 24-h ECG recording in Long COVID patients with postural orthostatic tachycardia syndrome, EP Europace, Volume 25, Issue Supplement_1, June 2023, euad122.626, https://doi.org/10.1093/europace/euad122.626 (Full text available as PDF file)

Autonomic Nervous System Affection Due to Post Covid Syndrome

Identification of the Effects of Post Covid Syndrome on the Autonomic Nervous System With Heart Rate Variability

Post-Covid syndrome is defined as symptoms that develop in addition to respiratory symptoms in individuals who have had Covid-19 infection for more than 12 weeks. Symptoms such as fatigue, headache, cognitive impairment, dyspnea, heart palpitations, heat intolerance, digestive system disorders, sleep disorders, dermal problems, orthostatic intolerance come to the fore in individuals with post-Covid syndrome. It has been tried to be revealed in some studies that Covid-19 infection affects the autonomic nervous system (ANS) and the relationship between Post-Covid 19 syndrome and ANS dysfunction.
Heart rate variability (HRV) measurement method can be used to evaluate ANS activity. HRV is a non-invasive method and is a measure of the change in heart rate over a period of time. HRV is a scalar quantity that shows the time between two beats of the heart and defines the oscillations between the R-R intervals. In HRV measurements, time-dependent and frequency-dependent measurement results are obtained and from these measurements, time-dependent RMSSD (square root of the square of the difference of the R-R intervals) and frequency-dependent high-frequency (HF) and low frequency (LF) measurement components are used in relation to the sympathetic nervous system (CNS) and parasympathetic nervous system (PSS). HRV can be measured in short-term (5 minutes) in terms of measurement time.
The aim of this study is to clearly reveal the relationship between Post-Covid 19 syndrome and ANS dysfunction and to provide standardization related to HRV measurement method and sub-parameters.
Source: Ali Veysel Özden, M.D. Bahçeşehir University. Istanbul, Beşiktaş, Turkey, 34000. ICH GCP US Clinical Trials Registry, Clinical Trial NCT05502094 https://ichgcp.net/clinical-trials-registry/NCT05502094

Parasympathetic autonomic dysfunction is more often evidenced than sympathetic autonomic dysfunction in fluctuating and polymorphic symptoms of “long-COVID” patients

Abstract:

Several disabling symptoms potentially related to dysautonomia have been reported in “long-COVID” patients. Unfortunately, these symptoms are often nonspecific, and autonomic nervous system explorations are rarely performed in these patients. This study aimed to evaluate prospectively a cohort of long-COVID patients presenting severe disabling and non-relapsing symptoms of potential dysautonomia and to identify sensitive tests.

Autonomic function was assessed by clinical examination, the Schirmer test; sudomotor evaluation, orthostatic blood pressure (BP) variation, 24-h ambulatory BP monitoring for sympathetic evaluation, and heart rate variation during orthostatism, deep breathing and Valsalva maneuvers for parasympathetic evaluation. Test results were considered abnormal if they reached the lower thresholds defined in publications and in our department. We also compared mean values for autonomic function tests between patients and age-matched controls.

Sixteen patients (median age 37 years [31–43 years], 15 women) were included in this study and referred 14.5 months (median) [12.0–16.5 months] after initial infection. Nine had at least one positive SARS-CoV-2 RT-PCR or serology result. Symptoms after SARS-CoV-2 infection were severe, fluctuating and disabling with effort intolerance. Six patients (37.5%) had one or several abnormal test results, affecting the parasympathetic cardiac function in five of them (31%). Mean Valsalva score was significantly lower in patients than in controls.

In this cohort of severely disabled long-COVID patients, 37.5% of them had at least one abnormal test result showing a possible contribution of dysautonomia to these nonspecific symptoms. Interestingly, mean values of the Valsalva test were significantly lower in patients than in control subjects, suggesting that normal values thresholds might not be appropriate in this population.

Source: Zanin, A., Amah, G., Chakroun, S. et al. Parasympathetic autonomic dysfunction is more often evidenced than sympathetic autonomic dysfunction in fluctuating and polymorphic symptoms of “long-COVID” patients. Sci Rep 13, 8251 (2023). https://doi.org/10.1038/s41598-023-35086-8 https://www.nature.com/articles/s41598-023-35086-8 (Full text)