VESTIBULAR DYSFUNCTIONS IN CHRONIC BRAIN ISCHEMIA IN THE POST COVID PERIOD.

OBJECTIVE: The aim: The aim of the study is the clinical-pathogenetic reasoning of vestibular dysfunctions (VD) development against the background of chronic brain ischemia in the presence of degenerative changes in the cervical spine (CS) in the post COVID period. PATIENTS AND METHODS: Materials and methods: 82 patients, in the conditions of the clinical base of the Odessa National Medical University in 2019-2021 were examined. Group I with VD against the background of chronic brain ischemia (CBI) at the compensated phase; Group II with VD against the background of CBI at the subcom¬pensated phase (33 men; 49 women), aged from 18 to 55 years. The control group (CG) consisted of 20 patients of the corresponding gender and age. The condition of the state of the autonomic nervous system, vestibular functions, cervical spine, cerebral arteries and emotional condition were examined. RESULTS: Results: Vestibulo-ataxic disorders were higher compared to CG and increased along with the degree of brain damage. An important aspect of the development of VD is autonomic dysfunction against the background of pathological autonomic characteristics with predominant parasympathetic orientation of autonomic tone, especially in the case of insufficiency of autonomic recativity (AR) and pathological autonomic support of activity. Such changes significantly increased in the presence of subcompensation of CBI. The correlation between psychoemotional disorders and changes in autonomic characteristics with VD against the background of CBI with initial regularities depending on the degree of brain damage was defined. The progression of CBI is facilitated by coronavirus infection and manifested in autonomic and psychoemotional dysfunctions. A characteristic hemodynamic feature in groups with compensated and subcompensated CBI is the presence of reduced perfusion in basilar (BA) and vertebral (VA) arteries. Changes in cerebral vascular reactivity with a decrease in cerebrovascular reactivity indicators were characteristic of the subcompensated phase of CBI. Hyperactivity to rotational functional loads in both clinical groups has a high correlation with the presence of stair descent and, to a lesser extent, isolated instability in CS. CONCLUSION: Conclusions: 1. The occurrence of VD is facilitated by the presence of autonomic dysfunction and degenerative-dystrophic changes in the CS, especially in case of subcompensation of CBI. 2. Psychoemotional changes were a characteristic feature of patients with VD against the background of CBI and had certain regularities depending on the phase of CBI. 3. Suffered coronavirus infection contributes to the progression of VD and further decompensation of CBI due to direct damage to the autonomic and vascular systems of the brain. 4. Changes in cerebral hemodynamics in the form of reduced perfusion in BA and VA, a decrease in cerebrovascular reactivity, and an increase in reactivity to rotational functional load were determined in patients with VD against the background of subcompensated CBI.

Investigating the possible mechanisms of autonomic dysfunction post-COVID-19.

Patients with long COVID suffer from many neurological manifestations that persist for 3 months following infection by SARS-CoV-2. Autonomic dysfunction (AD) or dysautonomia is one complication of long COVID that causes patients to experience fatigue, dizziness, syncope, dyspnea, orthostatic intolerance, nausea, vomiting, and heart palpitations. The pathophysiology behind AD onset post-COVID is largely unknown. As such, this review aims to highlight the potential mechanisms by which AD occurs in patients with long COVID. The first proposed mechanism includes the direct invasion of the hypothalamus or the medulla by SARS-CoV-2. Entry to these autonomic centers may occur through the neuronal or hematogenous routes. However, evidence so far indicates that neurological manifestations such as AD are caused indirectly. Another mechanism is autoimmunity whereby autoantibodies against different receptors and glycoproteins expressed on cellular membranes are produced. Additionally, persistent inflammation and hypoxia can work separately or together to promote sympathetic overactivation in a bidirectional interaction. Renin-angiotensin system imbalance can also drive AD in long COVID through the downregulation of relevant receptors and formation of autoantibodies. Understanding the pathophysiology of AD post-COVID-19 may help provide early diagnosis and better therapy for patients.

Clinical presentation and management strategies of cardiovascular autonomic dysfunction following a COVID-19 infection - A systematic review.

BACKGROUND: Cardiovascular autonomic dysfunction may reportedly occur after a coronavirus-disease-2019 (COVID-19) infection, but the available evidence is scattered. Here we sought to understand the acute and mid-term effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on cardiovascular autonomic function. METHODS: We performed a systematic PubMed, Embase, Web of Science, medRxiv, and bioRxiv search for cases of cardiovascular autonomic dysfunction during an acute SARS-CoV-2 infection or post-COVID-19 condition. The clinical-demographic characteristics of individuals in the acute versus post-COVID-19 phase were compared. RESULTS: We screened 6470 titles and abstracts. Fifty-four full-length articles were included in the data synthesis. One-hundred and thirty-four cases were identified: 81 during the acute SARS-CoV-2 infection (24 thereof diagnosed by history) and 53 in the post-COVID-19 phase. Post-COVID-19 cases were younger than those with cardiovascular autonomic disturbances in the acute SARS-CoV-2 phase (42 vs. 51 years old, p = 0.002) and were more frequently women (68% vs. 49%, p = 0.034). Reflex syncope was the most common cardiovascular autonomic disorder in the acute phase (p = 0.008) and postural orthostatic tachycardia syndrome (POTS) the most frequent diagnosis in individuals with post-COVID-19 orthostatic complaints (p < 0.001). Full recovery was more frequent in individuals with acute versus post-COVID-19 onset of cardiovascular autonomic disturbances (43% vs. 15%, p = 0.002). CONCLUSIONS: There is evidence from the scientific literature about different types of cardiovascular autonomic dysfunction developing during and after COVID-19. More data about the prevalence of autonomic disorders associated with a SARS-CoV-2 infection are needed to quantify its impact on human health.

Persistent Increase of Sympathetic Activity in Post-Acute COVID-19 of Paucisymptomatic Healthcare Workers.

Healthcare workers (HCWs) represent a population with a significant burden of paucisymptomatic COVID-19, as the general population. We evaluated autonomic nervous system activity by means of heart rate variability (HRV) in HCWs during health surveillance visits. Short-term electrocardiogram (ECG) recordings were obtained 30 days (IQR 5.25-55.75) after a negative naso-pharyngeal swab for SARS-CoV-2 in 44 cases and compared with ECGs of 44 controls with similar age and sex distribution. Time and frequency domain HRV were evaluated. HCWs who used drugs, had comorbidities that affected HRV, or were hospitalized with severe COVID-19 were excluded. Frequency domain HRV analysis showed a significantly higher low/high-frequency power ratio (LF/HF) in the case study compared with controls (t = 2.84, p = 0.006). In time domain HRV analysis, mean standard deviation of normal-to-normal intervals (SDNN) and root mean square of successive RR interval differences (RMSSD) were significantly lower for cases compared with controls (t = -2.64, p = 0.01 and t = -3.27, p = 0.002, respectively). In the post-acute phase of infection, SARS-CoV-2 produces an autonomic imbalance mirrored by a reduction in HRV. These results are consistent with epidemiological data that suggest a higher risk of acute cardiovascular complications in the first 30 days after COVID-19 infection.

Orthostatic Intolerance after COVID-19 Infection: Is Disturbed Microcirculation of the Vasa Vasorum of Capacitance Vessels the Primary Defect?

Following COVID-19 infection, a substantial proportion of patients suffer from persistent symptoms known as Long COVID. Among the main symptoms are fatigue, cognitive dysfunction, muscle weakness and orthostatic intolerance (OI). These symptoms also occur in myalgic encephalomyelitis/chronic fatigue (ME/CFS). OI is highly prevalent in ME/CFS and develops early during or after acute COVID-19 infection. The causes for OI are unknown and autonomic dysfunction is hypothetically assumed to be the primary cause, presumably as a consequence of neuroinflammation. Here, we propose an alternative, primary vascular mechanism as the underlying cause of OI in Long COVID. We assume that the capacitance vessel system, which plays a key role in physiologic orthostatic regulation, becomes dysfunctional due to a disturbance of the microvessels and the vasa vasorum, which supply large parts of the wall of those large vessels. We assume that the known microcirculatory disturbance found after COVID-19 infection, resulting from endothelial dysfunction, microthrombus formation and rheological disturbances of blood cells (altered deformability), also affects the vasa vasorum to impair the function of the capacitance vessels. In an attempt to compensate for the vascular deficit, sympathetic activity overshoots to further worsen OI, resulting in a vicious circle that maintains OI. The resulting orthostatic stress, in turn, plays a key role in autonomic dysfunction and the pathophysiology of ME/CFS.

Autonomic dysfunction and metabolic disorders as the possible sequelae of COVID-19 infection.

OBJECTIVE: The Coronavirus disease 2019 (COVID-19) infection is associated with autonomic dysfunction. Data on the long-term relationship between COVID-19 infection, heart rate recovery (HRR), and exaggerated blood pressure response to exercise (EBPR) are very limited. In our study, we aimed at investigating the long-term association between COVID-19, HRR, EBPR, metabolic, and echocardiographic parameters. PATIENTS AND METHODS: The study included 65 patients in the study group (33 female, median age 46) and 57 in the control group (30 female, 39 median age) between 1 April 2020 and 1 January 2021. Office blood pressure measurement, 24-hour ambulatory blood pressure monitoring, treadmill test, echocardiography, and metabolic parameters were evaluated. RESULTS: The frequency of blunted HRR (25 subjects, 38.5%, p < 0.001) and EBPR (7 subjects, 10.8%, p = 0.014) were significantly higher in study group. The study group had higher levels of white blood cell (p = 0.002), neutrophil, c-reactive protein, and uric acid (p < 0.001). Diameters of left atrium, aortic root, and ascending aorta were significantly higher in study group (p < 0.05). Age adjusted multiple logistic regression analysis showed that neutrophil levels (odds ratio (OR), 9.21; 95% confidence interval (CI), 1.52-55.75, p = 0.016), glomerular filtration rate (OR, 1.34; 95% CI, 1.13-1.59, p = 0.001), basal heart rate (OR, 1.58; 95% CI, 1.17-2.12, p = 0.003), and mean heart rate (OR, 1.22; 95% CI, 1.03-1.45, p = 0.0021) were independently associated with COVID-19 infection. CONCLUSIONS: The frequency of blunted HRR and EBPR, and uric acid levels were significantly higher in the study group compared to the control group, suggesting autonomic dysfunction as the possible sequelae of the COVID-19 infection and increased risk of cardiovascular events in the future.

Autonomic dysfunction in non-critically ill COVID-19 patients during the acute phase of disease: an observational, cross-sectional study.

INTRODUCTION: Evidence is emerging about an extra-pulmonary involvement of SARS-CoV-2, including the nervous system. Autonomic dysfunction in patients recovering from acute coronavirus disease 2019 (COVID-19) has been recently described. Dysautonomic symptoms have been reported in the acute phase of the disease, but clear evidence is lacking, especially in the non-critical forms of the infection. OBJECTIVE: The aim of this study is to assess the prevalence of dysautonomia in acute, non-critically ill COVID-19 patients. METHODS: In this observational, cross-sectional study, we compared 38 non-critically ill patients with acute COVID-19 (COVID + group) to 38 healthy volunteers (COVID - group) in order to assess the prevalence of signs and symptoms of dysautonomia through the administration of the composite autonomic symptom score 31 (COMPASS-31) and an active standing test. Comparisons between groups were performed by means of both univariate and multivariate analyses. RESULTS: The prevalence of orthostatic hypotension was significantly higher in the COVID + group. Higher total scores of COMPASS-31 were observed in the COVID + group than controls. Significant differences between groups emerged in the secretomotor, orthostatic intolerance, and gastrointestinal COMPASS-31 domains. All these results maintained the statistical significance after the adjustment for concomitant drugs with a known effect on the autonomic nervous system assumed by the study participants, except for the differences in the gastrointestinal domain of COMPASS-31. CONCLUSION: Our results suggest that an autonomic dysfunction could be an early manifestation of COVID-19, even in the contest of mild forms of the infection.

Autonomic dysfunction in patients with COVID­19.

PURPOSE: Autonomic dysfunction in patients with viral infections has been described before. In this study, we aimed to evaluate autonomic functions in patients with the coronavirus infectious disease 2019 (COVID-19). METHODS: In this cross-sectional study, we compared 112 patients who had recovered from COVID-19 and 106 healthy controls. Symptoms of autonomic dysfunction were assessed with the SCOPA-AUT scale. RESULTS: Pupillomotor, urinary and sudomotor subscores of SCOPA-AUT scale were significantly higher in the COVID-19 patient group (p = 0.03, p = 0,006, p = 0.0001, respectively). There were no significant difference in terms of gastrointestinal, cardiovascular, sexual subscores and total SCOPA-AUT scores between the patient and control groups. The presence of fatigue symptom in the acute phase of COVID-19 increased the total SCOPA-AUT score by 2.2 points (p = 0.04) whereas the presence of smell loss (OR = 5.82, p = 0.01) and dyspnea (OR = 5.8, p = 0.03) were significant risk factors for pupillomotor dysfunction. The urinary, cardiovascular, sexual subscores and the total score of SCOPA-AUT scale were positively correlated with the age of the patient group. CONCLUSION: Our study suggests that many patients might have prolonged symptoms of autonomic dysfunction after the acute phase of COVID-19 that might worsen the clinical recovery.

ROLE OF BODY MASS AND PHYSICAL ACTIVITY IN AUTONOMIC FUNCTION MODULATION ON POST-COVID-19 CONDITION: AN OBSERVATIONAL SUBANALYSIS OF FIT-COVID STUDY (preprint)

The harmful effects of coronavirus disease 2019 (COVID-19) can reach the autonomic nervous system (ANS) and endothelial function. Therefore, the detrimental multiorgan effects of COVID-19 could be induced by deregulations in ANS that may persist after the acute SARS-CoV-2 infection. Additionally, investigating the differences in ANS response in overweight/obese, and physically inactive participants who had COVID-19 compared to those who did not have the disease is necessary. The aim of the study was to analyze the autonomic function of young adults after mild-to-moderate infection with COVID-19 and to assess whether body mass index (BMI) and levels of physical activity modulates autonomic function in participants with and without COVID-19. Patients previously infected with COVID-19 and healthy controls were recruited for this cross-sectional observational study. A general anamnesis was taken and BMI and physical activity levels were assessed. The ANS was evaluated through heart rate variability. A total of 57 subjects were evaluated. Sympathetic nervous system activity in post-COVID-19 group was increased (stress index; p=0.0273). They also presented lower values of parasympathetic activity (p<0.05). Overweight/obese subjects in the post-COVID-19 group presented significantly lower parasympathetic activity and reduced global variability compared to non-obese in control group (p<0.05). Physically inactive subjects in post-COVID-19 group presented significantly higher sympathetic activity than active subjects in control group. Parasympathetic activity was significantly increased in physically active subjects in control group compared to the physically inactive post-COVID-19 group (p<0.05). COVID-19 promotes changes in the ANS of young adults, and these changes are modulated by Overweight/obesity and physical activity levels. Key Points ‐ Our main finding is that even in mild and moderate infections, young adults who had COVID-19 had greater sympathetic activity, less parasympathetic activity, and global variability when compared to uninfected individuals. ‐ In participants who were overweight and obese and/or physically inactive, cardiac autonomic modulation showed worse indices. ‐ Our study provides new insights regarding the role of body mass index and physical activity status on post-COVID-19 infection autonomic deregulation that may contribute to the understand of pathophysiology and treatment of of post-acute sequelae SARS-CoV-2 infection.

Heart rate variability changes in mild-symptomatic, physically fit male in 4-6 weeks from the end of SARS-Cov-2 infection (preprint)

SARS-Cov-2 infection, due to inflammation processes, can affect autonomic nervous system and heart rate variability (HRV) even after disease. Previous studies showed significant changes in HRV parameters in severe (including fatal) infection of SARS-Cov-2. However, HRV analysis for the asymptomatic or mild-symptomatic Covid-19 patients have not been reported. In this study, we suggested that there is an influence of a SARS-Cov-2 infection on the HRV in such patients after weeks form disease.Sixty-five ECG Holter recordings from young (mean age 22.6 ± 3.4 years), physically fit male subjects after 4-6 weeks from the second negative test (considered to be the beginning of recovery) and twenty-six control male subjects (mean age 23.2 ± 2.9 years) were considered in the study. Night-time RR time series were extracted from ECG signals. Selected linear, frequency as well as nonlinear HRV parameters were calculated. We found significant differences in Porta’s symbolic analysis parameters V0 and V2 (p<0.001), α 2 (p<0.001), very low frequency component (VLF; p=0.022), and respiratory peak (from PRSA method; p=0.012). These differences may be caused by the changes of the parasympathetic autonomic nervous system as well as by the coupling of respiratory rhythm with heart rate due to an increase in pulmonary arterial vascular resistance.The results suggest that the changes in the HRV, thus autonomic nervous system, are measurable after a few weeks from the beginning of the recovery even in the post-Covid group of young and physically active population. We indicated HRV sensitive markers which could be used in the long-term monitoring of recovered patients.

Syncope and COVID-19 disease - A systematic review.

BACKGROUND: Syncope is not a common manifestation of COVID-19, but it may occur in this context and it can be the presenting symptom in some cases. Different mechanisms may explain the pathophysiology behind COVID-19 related syncope. In this report, we aimed to examine the current frequency and etiology of syncope in COVID-19. METHODS: A systematic review across PubMed, ISI Web of Knowledge and SCOPUS was performed, according to PRISMA guidelines, in order to identify all relevant articles regarding both COVID-19 and syncope. RESULTS: We identified 136 publications, of which 99 were excluded. The frequency of syncope and pre-syncope across the selected studies was 4.2% (604/14,437). Unexplained syncope was the most common type (87.9% of the episodes), followed by reflex syncope (7.8% of the cases). Orthostatic hypotension was responsible for 2.2% of the cases and syncope of presumable cardiac cause also accounted for 2.2% of cases. Arterial hypertension was present in 52.0% of syncope patients. The use of angiotensin receptor blockers or angiotensin converting enzyme inhibitors were not associated with an increased incidence of syncope (chi-square test 1.07, p 0.30), unlike the use of beta-blockers (chi-square test 12.48, p < 0.01). CONCLUSION: Syncope, although not considered a typical symptom of COVID-19, can be associated with it, particularly in early stages. Different causes of syncope were seen in this context. A reevaluation of blood pressure in patients with COVID-19 is suggested, including reassessment of antihypertensive therapy, especially in the case of beta-blockers.

Autonomic dysfunction in SARS-COV-2 infection acute and long-term implications COVID-19 editor's page series.

The autonomic nervous system (ANS) is a complex network of nerves originating in the brain, brain stem, spinal cord, heart and extracardiac organs that regulates neural and physiological responses to internal and external environments and conditions. A common observation among patients with the 2019 Coronavirus (CoV) (SARS-severe acute respiratory syndrome CoV-2) (SARS-CoV-2) or COVID-19 [CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019)] in the acute and chronic phases of the disease is tachycardia, labile blood pressure, muscular fatigue and shortness of breath. Because abnormalities in the ANS can contribute to each of these symptoms, herein a review of autonomic dysfunction in SARS-COV-2 infection is provided to guide diagnostic testing, patient care and research initiatives. The autonomic nervous system is a complex network of nerves originating in the brain, brain stem, spinal cord, heart and extracardiac organs that regulates neural and physiological responses to internal and external environments and conditions. A common collection of signs and symptoms among patients with the 2019 Coronavirus (CoV) (SARS-severe acute respiratory syndrome CoV-2) (SARS-CoV-2) or COVID-19 [CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019)] is tachycardia, labile blood pressure, muscular fatigue and shortness of breath. Abnormalities in the autonomic nervous system (ANS) can contribute to each of these identifiers, potentially offering a unifying pathobiology for acute, subacute and the long-term sequelae of SARS-CoV-2 infection (PASC) and a target for intervention.

Autonomic dysfunction in post-COVID patients with and witfhout neurological symptoms: a prospective multidomain observational study.

The autonomic nervous system (ANS) can be affected by COVID-19, and dysautonomia may be a possible complication in post-COVID individuals. Orthostatic hypotension (OH) and postural tachycardia syndrome (POTS) have been suggested to be common after SARS-CoV-2 infection, but other components of ANS function may be also impaired. The Composite Autonomic Symptom Scale 31 (COMPASS-31) questionnaire is a simple and validated tool to assess dysautonomic symptoms. The aim of the present study was to administer the COMPASS-31 questionnaire to a sample of post-COVID patients with and without neurological complaints. Participants were recruited among the post-COVID ambulatory services for follow-up evaluation between 4 weeks and 9 months from COVID-19 symptoms onset. Participants were asked to complete the COMPASS-31 questionnaire referring to the period after COVID-19 disease. Heart rate and blood pressure were manually taken during an active stand test for OH and POTS diagnosis. One-hundred and eighty participants were included in the analysis (70.6% females, 51 ± 13 years), and OH was found in 13.8% of the subjects. Median COMPASS-31 score was 17.6 (6.9-31.4), with the most affected domains being orthostatic intolerance, sudomotor, gastrointestinal and pupillomotor dysfunction. A higher COMPASS-31 score was found in those with neurological symptoms (p < 0.01), due to more severe orthostatic intolerance symptoms (p < 0.01), although gastrointestinal (p < 0.01), urinary (p < 0.01), and pupillomotor (p < 0.01) domains were more represented in the non-neurological symptoms group. This study confirms the importance of monitoring ANS symptoms as a possible complication of COVID-19 disease that may persist in the post-acute period.

Syncope and silent hypoxemia in COVID-19: Implications for the autonomic field.

Coronavirus-19 (COVID-19), the infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has wreaked havoc across the globe since its emergence in December 2019. Reports of patients presenting with syncope and pre-syncope, as well as hypoxemia without symptoms of dyspnea ("silent hypoxemia"), have led researchers to speculate whether SARS-CoV-2 can alter autonomic nervous system function. As viral infections are commonly reported triggers of altered autonomic control, we must consider whether SARS-CoV-2 can also interfere with autonomic activity, at least in some patients. As we are still in the early stages of understanding COVID-19, we still do not know whether syncope and silent hypoxemia are more strongly associated with COVID-19 compared to any other viral infections that severely compromise gas exchange. Therefore, in this perspective we discuss these two intriguing clinical presentations, as they relate to autonomic nervous system function. In our discussion, we will explore COVID-specific, as well as non-COVID specific mechanisms that may affect autonomic activity and potential therapeutic targets. As we move forward in our understanding of COVID-19, well-designed prospective studies with appropriate control and comparator groups will be necessary to identify potential unique effects of COVID-19 on autonomic function.

Preparing for the long-haul: Autonomic complications of COVID-19.

As global numbers of COVID-19 grow, chronic neurological symptoms, including those of autonomic dysfunction, are being reported with increasing frequency. Mounting evidence suggests that many patients experience chronic and sometimes debilitating symptoms long after their acute infectious period, leading to the new diagnostic category of post-acute COVID syndrome. Many symptoms of post-acute COVID syndrome appear autonomic in nature, suggesting that autonomic impairment may play a central role in the underlying pathophysiology. In this review, we discuss the autonomic symptoms and manifestations of post-acute COVID syndrome, potential mechanisms involved, and future directions for a better understanding of this novel condition.