COMPASS-31 Score Research Articles

Autonomic nervous system dysfunction in idiopathic REM sleep behavior disorder as a short-term risk for a synucleinopathy.

Idiopathic REM sleep behavior disorder (iRBD) is a prodromal marker of the alpha-synucleinopathies, in which autonomic nervous system (ANS) involvement may occur. We aimed to characterize the presence and severity of subjective and objective ANS dysfunction in iRBD and assess its capacity to predict short-term clinical progression to a synucleinopathy. Prospective study of patients with polysomnography-confirmed iRBD in whom symptomatic ANS involvement was assessed using the Composite Autonomic Symptom Score (COMPASS-31) and objective dysfunction with the Composite Autonomic Severity Score (CASS). Baseline ANS data were compared between those who later developed a synucleinopathy and those who did not. We evaluated 25 subjects with iRBD without risk factors for autonomic neuropathy and at least 6months of follow-up (mean: 19months). At the end of the study, seven (28%) patients developed a synucleinopathy, namely Parkinson's disease (n = 5) and dementia with Lewy bodies (n = 2). 73.7% of patients had COMPASS-31 scores above the normal cut-off, while no score differences regarding phenoconversion status were observed. At baseline, 85.7% of the subjects who phenoconverted exhibited at least one abnormal result in the CASS score, compared to 38.9% of subjects who remained disease-free (p = 0.035). Adrenergic dysfunction evaluated by an impaired overshoot in Valsalva phase IV and by pressure recovery time was associated with the development of overt synucleinopathy (p = 0.032 and 0.033, respectively). Symptomatic and subclinical ANS dysfunctions are common in iRBD. ANS dysfunction affecting mainly the adrenergic system seems to be a short-term risk for the development of a synucleinopathy.

Treatment of Post-COVID-19 POTS by inhibiting FcRn: a phase 2 randomized, placebo controlled, double-blind, proof of concept study with efgartigimod

Abstract Background While the underlying pathophysiology is unknown, post–COVID-19 postural orthostatic tachycardia syndrome (POTS) may be related to immune dysfunction and autoimmunity precipitated by SARS-CoV-2 infection. Various autoantibodies, including those targeting G-protein coupled receptors (GPCRs), have been observed in patients with POTS. Binding of these autoantibodies to adrenergic receptors, which are prototypical GPCRs, has been hypothesized to modulate receptor activity, increase sympathetic tone, and cause tachycardia. Moreover, IgG anti-GPCR autoantibodies, acting as partial agonists, are thought to decrease the effect of peripheral vasomotor control, leading to an increased sympathetic response to upright posture that can result in postural tachycardia in the absence of hypotension. Purpose We hypothesize that a reduction in autoantibody levels by efgartigimod, a FcRn-antagonist, will ameliorate the underlying immune-mediated pathogenesis and lead to clinical improvements in patients who developed POTS following COVID-19 infection. We propose a phase II multicenter, randomized, placebo-controlled, double-blind, proof-of-mechanism study initiated to evaluate the safety and efficacy of efgartigimod in adults with post–COVID-19 POTS. Methods Adult patients diagnosed with new-onset of POTS following SARS-CoV-2 infection are eligible for participation in the study. Prior COVID-19 must be confirmed by documentation of historical PCR test, and POTS diagnosis must meet consensus criteria. Study subjects must have moderate to severe autonomic symptoms (COMPASS-31 score ≥ 35 points at screening). Approximately 42 patients will be randomly allocated (2:1) to receive weekly intravenous efgartigimod or placebo for 24 weeks. At the end of the treatment period, participants who complete the study may roll over into an open-label extension (OLE). The co-primary endpoints are change from baseline to week 24 in the COMPASS-31 and Malmo POTS Symptom Score as well as safety and tolerability outcomes. Key secondary endpoints include assessments of disease activity, fatigue, cognitive function, walking capacity and quantitative autonomic testing. Additional exploratory endpoints include intraepidermal small fiber densities (optional), sudomotor innervation (optional) and peripheral blood biomarkers to define histopathological and immune determinants associated with treatment response. Conclusions This phase II study of efgartigimod will evaluate the effect of FcRn inhibition on disease pathology and the potential for therapeutic benefit in patients with post–COVID-19 POTS.

An evaluation of autonomic and gastrointestinal symptoms, and gastric emptying, in patients with systemic sclerosis.

Assessment of gastrointestinal and autonomic symptoms in patients with systemic sclerosis, and possible associations with gastric emptying rate. Participant and patient disease-related characteristics were collected. Gastrointestinal and autonomic symptoms were assessed by the UCLA-SCTC GIT 2.0 and COMPASS-31 questionnaires, respectively. Potentially confounding gastrointestinal medications were discontinued where possible. Gastric emptying was assessed using a non-radioactive 13C sodium acetate isotope, end-expiratory breath samples collected at baseline and then serial timepoints up to 120 min. In total, 49 participants were studied: 17 with systemic sclerosis with variable gastrointestinal involvement, and healthy matched (n = 17) and non-matched controls (n = 15), the last to control for the impact of age rather than disease on gastric emptying and autonomic function. The total mean (range) UCLA GIT 2.0 questionnaire for patients with systemic sclerosis was 0.63 (0.0-1.5) and for both healthy matched and non-matched controls was 0.04 (0.0-0.2), and was higher in patients with systemic sclerosis across all domains. The total mean (range) COMPASS-31 score for patients with systemic sclerosis patients was 32.2 (0.0-54.9) and for healthy matched- and non-matched controls: 7.45 (0.0-24.9) and 4.25 (0.0-2.1), respectively, again higher for patients with systemic sclerosis across all domains. No association was observed between patients' UCLA GIT 2.0 total score (s = -0.039, p = 0.38), total COMPASS 31 score (s = -0.108, p = 0.68), or COMPASS-31 GI domain (s = -0.051, p = 0.85) and gastric emptying rates. Gastrointestinal and autonomic symptoms are overrepresented in patients with systemic sclerosis but did not associate with gastric emptying rates.

Evaluating the Associations Among Dysautonomia, Gastrointestinal Transit, and Clinical Phenotype in Patients With Systemic Sclerosis.

Our objective was to identify patients with systemic sclerosis (SSc) with a high burden of autonomic symptoms and to determine whether they have a distinct clinical phenotype, gastrointestinal (GI) transit, or extraintestinal features. In a prospective cohort of patients with SSc with GI disease, clinical data were systematically obtained at routine visits. Dysautonomia was identified by the Composite Autonomic Symptom Score (COMPASS)-31questionnaire. GI transit was measured by whole-gut scintigraphy. Associations between total COMPASS-31 scores and clinical features, GI symptoms, and transit were evaluated. Comparisons between patients with global autonomic dysfunction (GAD; ≥5 positive COMPASS-31 subdomains) and those with limited autonomic dysfunction (LAD; <5 positive subdomains) were also studied. A total of 91 patients with SSc and GI involvement were included (mean age 57 years, 90% female, 74% limited cutaneous disease, 83% significant GI disease [Medsger score ≥2]). The mean COMPASS-31 score in patients with SSc was higher than controls (38.8 vs 7.2); 33% had GAD, and 67% had LAD. Patients with GAD were more likely to have limited SSc (93% vs 65%; P < 0.01) and have sicca symptoms (100% vs 77%; P = 0.01). Gastric and colonic transit were faster in patients with GAD (P < 0.05). Upper GI involvement (Medsger GI score of 1 or 2) was associated with higher total COMPASS-31 scores (P = 0.02). Symptoms of global dysautonomia are seen in up to one-third of patients with SSc and GI involvement. Identifying specific clinical characteristics associated with GAD in SSc will help to identify a population that may benefit from therapies that modulate the autonomic nervous system.

Genetic mutations in Parkinson's disease: screening of a selected population from North-Eastern Italy.

Parkinson's disease (PD) is a progressive neurodegenerative disorder with a multifactorial pathogenesis. Several genetic variants increase the risk of PD and about 5-10% of cases are monogenic. This study aims to define the genetic bases and clinical features of PD in a cohort of patients from Northeastern Italy, a peculiar geographical area previously not included in genetic screenings. Using an NGS multigenic panel, 218 PD patients were tested based on age at onset, family history and development of atypical features. A total of 133 genetic variants were found in 103 patients. Monogenic PD was diagnosed in 43 patients (20% of the cohort); 28 (12.8%) carried mutations in GBA1, 10 in LRRK2 (4.6%) and 5 in PRKN (2.3%). In 17% of patients the genetic defect remained of uncertain interpretation. The selection criterion "age of onset < 55years" was a significant predictor of a positive genetic test (OR 3.8, p 0.0037). GBA1 patients showed more severe symptoms and a higher burden of motor and non-motor complications compared to negative patients (dyskinesias OR 3, sleep disturbances OR 2.8, cognitive deficits OR 3.6; p < 0.05), with greater autonomic dysfunction (COMPASS-31 score 34.1 vs 20.2, p 0.03). Applying simple clinical criteria for genetic testing allows to increase the probability to identify patients with monogenic PD and better allocate resources. This process is critical to widen the understanding of disease mechanisms and to increase the individuation of patients potentially benefitting from future disease-modifying therapies.

Autonomic dysfunction is prevalent in PASC of Covid-19 [PASC

Abstract Background Post-acute sequelae of COVID-19 [PASC] is thought to occur in 10% of all COVID infections and has previously been associated with autonomic dysfunction including postural orthostatic tachycardia syndrome [POTS].[1,2] Purpose To assess prevalence of autonomic disorders in those with PASC. Methods Consecutive patients reporting unexplained symptoms persisting for ≥3 months after SARS-CoV-2 infection were recruited through social media platforms. Beat to beat plethysmography was used to determine autonomic haemodynamic response to 10-minute active stand test, Valsalva maneuverer and deep breathing. International criteria were used to diagnose POTS, initial orthostatic hypotension (IOH), and classical orthostatic hypotension (COH). Validated patient reported outcome measures were used to determine symptom severity and health related quality of life (HrQoL) including, composite autonomic symptom score [COMPASS-31], Euroquol 5-Dimension [EQ-5D] and fatigue severity score (FSS). Results Institutional ethics was granted from our university. A total of 150 PASC participants (79% female, 93% Caucasian) with a mean age of 40.7 ± 11.5 years and BMI 25.8 ± 6.7 were prospectively consented and enrolled. In total 86% were vaccinated with at least 2 vaccines at the time of acute SARS-CoV-2 infection. The mean time to onset of PASC symptoms after acute infection was 18.3 ± 35.3 days and duration of symptoms at time of testing was 306.9 ± 188.1 days. In total 75% of participants met the criteria for an autonomic disorder with the most common diagnoses being POTS (55%), initial orthostatic hypotension (38%), and classic orthostatic hypotension (5%) respectively. Valsalva ratio was within normal limits for the majority (90%) of participants however it was statistically higher in those with POTS compared to those without (1.9±.6 versus 1.7±.8: p=.014). Total composite autonomic symptoms were more severe in women than men (42.6±13.1 vs. 35.4±19.9; p = .018) and those with a COMPASS-31 score &amp;gt;40 (49%) had worse fatigue severity (57.9±6.9 vs. 50.3±14.3: p&amp;lt;.001) and poorer EQ-5D utility health scores (0.611±0.247 vs 0.701±0.237: p =.008) on a scale from 0-1 where ‘1’ = ‘full health’. The mean FSS score was 53.9±11.8 out of a maximum score of 63 and fatigue was universally problematic with 92% experiencing FSS score &amp;gt;36. Participants reported only being a mean of 40.5%±21.2% of their previous health status and the mean self-reported ‘health today’ [100 = ‘full health’] was 40.5 ± 14.2. A significant 91.3% reported missing work due to symptoms in the last month and 50.3% had been unable to return to work due to PASC symptoms. Conclusion Autonomic disorders are prevalent in PASC and greatly impact on working capacity and health related quality of life. We call for routine autonomic testing in PASC and further research to explore efficacy of autonomic treatment modalities in this cohort.

Symptomatic Autonomic Dysfunction in Interstitial Cystitis/Bladder Pain Syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a highly prevalent condition with incompletely understood pathophysiology, especially in relation to the systemic symptoms experienced. The role of autonomic nervous system dysfunction in IC/BPS remains poorly understood. The purpose of this study was to assess the relationship between autonomic symptom severity and clinical characteristics of patients with IC/BPS. This is a retrospective cohort study of 122 IC/BPS patients who completed the Composite Autonomic Symptoms Score (COMPASS-31) questionnaire. Data were collected on anesthetic bladder capacity (BC), Hunner lesion (HL) status, results for validated IC/BPS symptom questionnaires (O'Leary Sant Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index (ICSI/ICPI) and the Pelvic Pain and Urgency/Frequency (PUF) scale), and comorbid nonurologic associated syndromes. Using the first quartile of COMPASS-31 scores as the cutoff, we compared patients within the first quartile (low symptom load; n = 30), to the remainder of the patients (high symptom load; n = 92). Patients scoring ≥20.36 were significantly less likely to be HL positive (10.9% vs 26.7%; P = 0.043) and had a significantly higher BC (823.10 ± 396.07 vs 635.00 ± 335.06; P = 0.027), higher scores on the PUF questionnaire (23.80 ± 4.98 vs; 19.61 ± 5.22 P < 0.001), and a higher number of nonurologic associated syndromes (5.65 ± 2.90 vs 2.60 ± 1.89; P < 0.001). Patients with IC/BPS experience widespread symptoms associated with autonomic nervous system dysfunction. A higher symptom load strongly correlates with a nonbladder-centric phenotype. These findings provide further evidence that total body nervous system dysfunction is present in patients with nonbladder centric IC/BPS.

Association between COVID-19 exposure and autonomic nervous system dysfunction in apparently healthy adults: an observational study.

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. 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". 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. 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.

Cardiovascular Symptoms, Dysautonomia, and Quality of Life in Adult and Pediatric Patients with Hypermobile Ehlers-Danlos Syndrome: A Brief Review.

Hypermobile Ehlers-Danlos Syndrome (hEDS) is a connective tissue disorder characterized by joint hypermobility and other systemic manifestations, such as cardiovascular symptoms, musculoskeletal pain, and joint instability. Cardiovascular symptoms, such as lightheadedness and palpitations, and types of dysautonomia, including postural orthostatic tachycardia syndrome (POTS), are frequently reported in adults with hEDS and have been shown to negatively impact quality of life (QoL). This brief review will be an overview of co-occurring symptoms in POTS and hEDS to inform potential cardiovascular screening procedures. While many patients with hEDS report cardiovascular symptoms, few have structural abnormalities, suggesting that dysautonomia is likely responsible for these symptoms. One validated screening measure for dysautonomia symptom burden is the Composite Autonomic Symptom Scale (COMPASS-31). Studies have found that adults with POTS, hEDS, and both POTS and hEDS have higher COMPASS-31 scores than the general population, suggesting a high symptom burden due to dysautonomia, which leads to impaired QoL. While studies have examined cardiovascular symptoms and the impact of dysautonomia in adults with and without hEDS, there is scant literature on dysautonomia in pediatric patients with hEDS. Therefore, more studies on cardiovascular symptoms and dysautonomia, as they relate to the quality of life in pediatric patients with hEDS, are needed. This brief review summarizes the current literature on dysautonomia and cardiovascular symptoms in pediatric and adult populations with hEDS.

Analysis of the correlation between heart rate variability and palpitation symptoms in female patients with long COVID.

To analyze the correlation between heart rate variability (HRV) and palpitation symptoms in female patients with long COVID. A total of 272 female healthcare workers who were infected with SARS-CoV-2 for the first time in December 2022 at Fuzhou First Hospital affiliated with Fujian Medical University, were selected as study subjects. These subjects were divided into three groups based on their symptoms: a group with palpitations (70 cases), a group without palpitations but with other symptoms (124 cases), and a group consisting of asymptomatic cases (78 cases). The study compared the general information, COMPASS-31 scores, quality of life scores, and HRV parameters among the three groups. Furthermore, it analyzed the factors influencing palpitation symptoms in female patients with long COVID. Compared to the other two groups, the HRV parameters SDNN, HRVIndex, LF, and TP were significantly reduced in the group with palpitations (p < 0.05). Multivariate analysis revealed that HRVIndex (p = 0.016; OR: 0.966, 95% CI: 0.940∼0.994) had a significant impact on palpitation symptoms in female patients with long COVID. The symptoms of palpitations in female patients with long COVID were found to be related to HRV parameters. Autonomic dysfunction may be connected to the occurrence of palpitation symptoms in long COVID.

Quantification of Dysautonomia in Major Depressive Disorder Using the Composite Autonomic Scoring Scale-31 (COMPASS-31).

Background Dysautonomia denotes an alteration in the autonomic nervous system that can significantly lead to multiorgan failure. Conversely, depression not only affects cognitive functions but also poses a risk factor for sudden cardiac death. In our study, the Composite Autonomic Scoring-31 (COMPASS-31) is used to quantify the autonomic symptoms present if any in patients with depression. Materials and methods Forty-two patients with major depressive disorder (MDD) were recruited using a PHQ-9 questionnaire followed by a COMPASS-31 scale to quantify dysautonomia symptoms, and they were compared with healthy controls. Further regression analysis was conducted to establish any relationship between independent variables and COMPASS-31 scores. Results The average COMPASS-31 score in patients with MDD was 22.56±8.42, which was significantly increased compared to healthy controls (p=0.001).Furthermore, the differences persisted across various subdomains of the COMPASS-31 scale relative to severity of depression. Conclusion The study observations could provide a relevant perception regarding the association between depressionand autonomic dysfunction with the use of a simple and brief yet validated instrument COMPASS-31, which can be utilized for screening at the primary care level.

Increased gut permeability and bacterial translocation are associated with fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome: implications for disease-related biomarker discovery.

There is growing evidence of the significance of gastrointestinal complaints in the impairment of the intestinal mucosal barrier function and inflammation in fibromyalgia (FM) and in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, data on intestinal permeability and gut barrier dysfunction in FM and ME/CFS are still limited with conflicting results. This study aimed to assess circulating biomarkers potentially related to intestinal barrier dysfunction and bacterial translocation and their association with self-reported symptoms in these conditions. A pilot multicenter, cross-sectional cohort study with consecutive enrolment of 22 patients with FM, 30 with ME/CFS and 26 matched healthy controls. Plasma levels of anti-beta-lactoglobulin antibodies (IgG anti-β-LGB), zonulin-1 (ZO-1), lipopolysaccharides (LPS), soluble CD14 (sCD14) and interleukin-1-beta (IL-1β) were assayed using ELISA. Demographic and clinical characteristics of the participants were recorded using validated self-reported outcome measures. The diagnostic accuracy of each biomarker was assessed using the receiver operating characteristic (ROC) curve analysis. FM patients had significantly higher levels of anti-β-LGB, ZO-1, LPS, and sCD14 than healthy controls (all P < 0.0001). In ME/CFS patients, levels of anti-β-LGB, ZO-1, LPS, and sCD14 were significantly higher than controls, but lower than in FM (all P < 0.01), while there was no significant difference in IL-1β level. In the FM and ME/CFS cohorts, both anti-β-LGB and ZO-1 correlated significantly with LPS and sCD14 (P < 0.001 for both). In the FM group, both anti-β-LGB and ZO-1 were correlated significantly with physical and mental health components on the SF-36 scale (P < 0.05); whereas IL-1β negatively correlated with the COMPASS-31 score (P < 0.05). In the ME/CFS cohort, ZO-1 was positively correlated with the COMPASS-31 score (P < 0.05). The ROC curve analysis indicated a strong ability of anti-β-LGB, ZO-1, LPS and sCD14 to predictively distinguish between FM and ME/CFS from healthy controls (P < 0.0001). Biomarkers of intestinal barrier function and inflammation were associated with autonomic dysfunction assessed by COMPASS-31 scores in FM and ME/CFS respectively. Anti-β-LGB antibodies, ZO-1, LPS, and sCD14 may be putative predictors of intestinal barrier dysfunction in these cohorts. Further studies are needed to assess whether these findings are causal and can therefore be applied in clinical practice.

Alterations in short-term blood pressure variability related to disease severity and autonomic symptoms in myasthenia gravis patients

ObjectivesWe aimed to evaluate beat-to-beat blood pressure variability (BPV) during head-up tilt test (HUTT) in patients with mild and moderate myasthenia gravis (MG) compared to healthy controls (HCs), and its association with the severity of autonomic symptoms.MethodsA total of 50 MG patients and 30 HCs were evaluated. Patients were stratified into 2 groups regarding Myasthenia Gravis Foundation of America (MGFA) classification: mild (I,II MGFA), moderate form (III MGFA). Autonomic symptoms were assessed by COMPASS-31 questionnaire. Cardiovascular parameters, indices of very short-term systolic (SBPV), and diastolic blood pressure (BP) variability (DBPV) were assessed at rest, and during HUTT.ResultsModerate MG patients were characterized by an overall shift of sympathovagal balance toward sympathetic predominance, either at rest and during HUTT, as well as lower values of high frequency (HFnu) of DBPV during HUTT, compared to HCs and mild MG. Similarly, moderate MG showed higher resting low frequency (LFnu) of DBPV (p=0.035), higher COMPASS-31 score (p=0.031), and orthostatic intolerance sub-score (p=0.019) than mild MG patients. Compared to HCs, mild MG patients showed lower Δmean BP (p=0.029), Δdiastolic BP (p=0.016). Autonomic symptoms were associated with lower BP values, at rest and during HUTT, and lower LF BPV parameters during HUTT.ConclusionMG patients present significant alterations in BPV, both at rest and in response to orthostatic stress, which are related to autonomic symptoms and disease severity. This study confirms the importance of monitoring BPV when evaluating cardiovascular autonomic function and its evolution over the course of MG disease.

Autonomic dysregulation, cognition and fatigue in people with depression and in active and healthy controls: observational cohort study

Background Autonomic nervous system (ANS) dysregulation might be relevant to the pathophysiology of fatigue and cognitive impairment in depression and perhaps should be considered when making prescribing decisions. Aims To determine the relationship of self-reported ANS symptoms with fatigue, cognition and prescribed medication in people with a diagnosis of depression, in comparators without depression but with other mental health, neurodevelopmental or neurodegenerative disorders (active controls) and in healthy controls. Method Cross-sectional analysis of an opportunistic sample from England. Self-reported data were collected on demographics, diagnosis, medication, ANS symptoms (Composite Autonomic Symptom Scale-31, COMPASS-31) and fatigue (Visual Analogue Scale for Fatigue, VAS-F). A subsample completed cognitive tests (THINC-it), including the subjective Perceived Deficits Questionnaire five-item version (PDQ-5). Spearman's correlation and mediation models were used to explore the relationship between COMPASS-31, VAS-F and PDQ-5 scores. Results Data were obtained for 3345 participants, 22% with depression. The depression group had significantly (P &lt; 0.01) more severe autonomic dysregulation as measured by COMPASS-31 scores (median 30) than active (median 23) and healthy controls (median 10). The depression group had significantly higher symptom severity (P &lt; 0.01) than both control groups on the VAS-F and PDQ-5. Overall, there was a significantly positive correlation (P &lt; 0.01) between COMPASS-31, VAS-F scores (Spearman's rho rs = 0.44) and PDQ-5 scores (rs = 0.56). COMPASS-31 scores mediated greater symptom severity on the VAS-F and PDQ-5 for those with depression. COMPASS-31 scores remained significantly different between the depression group and both control groups independently of medication. Conclusions People with a diagnosis of depression report worse fatigue and cognition than active and healthy comparators; this appears to be mediated by ANS dysregulation.

High Incidence of Autonomic Dysfunction and Postural Orthostatic Tachycardia Syndrome in Patients with Long COVID: Implications for Management and Health Care Planning

BackgroundAutonomic 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. MethodsAll participants were prospectively enrolled between August 5, 2021 and October 31, 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. ResultsA total of 99 participants (n = 33 PASC, n = 33 POTS, and n = 33 healthy controls; median age 32 years, 85.9% females) were included. Compared with healthy controls, the PASC and POTS cohorts demonstrated significantly reduced respiratory sinus arrhythmia (P < .001), greater heart rate increase during 10-minute active standing test (P < .001), greater burden of autonomic dysfunction evidenced by higher COMPASS-31 scores across all subdomains (all P < .001), and poor HrQoL across all EQ-5D-5L domains (all P < .001), lower median EuroQol-visual analogue scale (P < .001), and lower utility scores (P < .001). The majority (79%) of those with PASC met the internationally established criteria for POTS. ConclusionThe prevalence of autonomic symptomology for 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.

Minimal Objective Autonomic Dysfunction in Long-COVID (S43.004)

<h3>Objective:</h3> Our aim was to characterize autonomic symptoms, severity and objective measures of autonomic function in patients with post-COVID syndrome. <h3>Background:</h3> Many patients report persistent symptoms that continue beyond the acute phase of COVID-19 (SARS-CoV-2) infection, variably called “long-COVID”, “post-COVID”, or “long-haul COVID”. Common symptoms include fatigue, orthostatic intolerance, cognitive impairment, and syncope, similar to the symptom profile of POTS. Although highly prevalent (affects 33–87% of hospitalized and 37% of non-hospitalized COVID patients), the pathophysiology of long-COVID is still not well understood. It is speculated that long-COVID patients have POTS or some other immune-mediated dysautonomia. <h3>Design/Methods:</h3> Retrospective analysis approved by UT Southwestern IRB. We identified 50 patients from our large COVID Recover clinic who were referred to the UT Southwestern autonomic laboratory for testing. Prior to testing, all patients were evaluated with supine and standing orthostatic vitals and completed symptom questionnaires. <h3>Results:</h3> Of 50 long-COVID patients who underwent standard autonomic testing, 24 patients had normal testing, 6 met heart rate criteria for POTS (by tilt table), 1 had severe diffuse autonomic failure with neurogenic orthostatic hypotension, 3 had mild length-dependent sudomotor impairment, 8 had mildly abnormal testing attributable to medication effects, 10 had mild non-specific autonomic impairment. The median CASS score was 0 (mean 1.0, range 0–8). The mean COMPASS-31 score was 43.4 (n= 43 patients), indicating severe symptoms. This score was similar in severity to previously studied POTS cohort (COMPASS 31 46.01, n= 205). <h3>Conclusions:</h3> Although these long-COVID patients had severe symptoms, majority of patients had normal autonomic function tests or non-specific mild abnormalities (86%). Only 12% had testing consistent with POTS, 20% had mild non-specific autonomic dysfunction, and 2% had significant autonomic failure. This is the largest cohort to date of autonomic testing in patients with long-COVID. Long-COVID symptoms are usually not associated with POTS or other clear evidence of autonomic dysfunction. <b>Disclosure:</b> The institution of Dr. Bryarly has received research support from Theravance. Dr. Cabrera has nothing to disclose. Dr. Barshikar has received publishing royalties from a publication relating to health care. Dr. Vernino has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amneal. Dr. Vernino has received personal compensation in the range of $500-$4,999 for serving as a Consultant for argenx. Dr. Vernino has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Vernino has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alterity. Dr. Vernino has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for LabCorp. Dr. Vernino has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for argenx. Dr. Vernino has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Autonomic Neuroscience (Elsevier). The institution of Dr. Vernino has received research support from Grifols. The institution of Dr. Vernino has received research support from Dysautonomia International. The institution of Dr. Vernino has received research support from BioHaven. The institution of Dr. Vernino has received research support from Takeda. Dr. Vernino has received personal compensation in the range of $10,000-$49,999 for serving as a Content Expert Consultant with Office of Inspector General for Medicare.

Case series: Maraviroc and pravastatin as a therapeutic option to treat long COVID/Post-acute sequelae of COVID (PASC).

Post-acute sequelae of COVID (PASC), or long COVID, is a multisystem complication of SARS-CoV-2 infection that continues to debilitate millions worldwide thus highlighting the public health importance of identifying effective therapeutics to alleviate this illness. One explanation behind PASC may be attributed to the recent discovery of persistent S1 protein subunit of SARS-CoV-2 in CD16+ monocytes up to 15 months after infection. CD16+ monocytes, which express both CCR5 and fractalkine receptors (CX3CR1), play a role in vascular homeostasis and endothelial immune surveillance. We propose targeting these receptors using the CCR5 antagonist, maraviroc, along with pravastatin, a fractalkine inhibitor, could disrupt the monocytic-endothelial-platelet axis that may be central to the etiology of PASC. Using five validated clinical scales (NYHA, MRC Dyspnea, COMPASS-31, modified Rankin, and Fatigue Severity Score) to measure 18 participants' response to treatment, we observed significant clinical improvement in 6 to 12 weeks on a combination of maraviroc 300 mg per oral twice a day and pravastatin 10 mg per oral daily. Subjective neurological, autonomic, respiratory, cardiac and fatigue symptoms scores all decreased which correlated with statistically significant decreases in vascular markers sCD40L and VEGF. These findings suggest that by interrupting the monocytic-endothelial-platelet axis, maraviroc and pravastatin may restore the immune dysregulation observed in PASC and could be potential therapeutic options. This sets the framework for a future double-blinded, placebo-controlled randomized trial to further investigate the drug efficacy of maraviroc and pravastatin in treating PASC.

Immunotherapy With Subcutaneous Immunoglobulin or Plasmapheresis in Patients With Postural Orthostatic Tachycardia Syndrome (POTS)

Objective To assess improvement in autonomic symptoms and functional impairment following immunotherapy with subcutaneous immunoglobulin (SCIG) or plasmapheresis (PLEX) in patients with postural orthostatic tachycardia syndrome (POTS). Background POTS is a common autonomic disorder defined by an increased heart rate of at least 30 bpm within 10 minutes of standing or a tilt table test, accompanied by orthostatic intolerance, fatigue, dizziness, and headache. Despite pharmacologic and non-pharmacologic therapy, the marked functional impairment associated with POTS reflects great need for improved treatment. Autoimmunity has emerged as a leading etiology of POTS, with case series describing successful treatment with IVIG. To our knowledge, treatment with SCIG has not been described previously. Design/Methods Clinical history of seven patients with POTS treated with SCIG or PLEX was reviewed. Response to treatment was assessed using COMPASS-31 and functional ability scale (FAS) completed retrospectively pre- and 3-12 months post-treatment with SCIG or PLEX. Patients with comorbid defined autoimmune disorders or immune deficiency requiring treatment with immunotherapy were excluded from the study. Results Of seven patients, all female, ages 28-57, five received SCIG and two received PLEX. Four had comorbid small fiber neuropathy and five had various positive antibodies at low titers. Across all patients, COMPASS-31 and FAS scores improved an average of 50% and 217%, respectively. Six patients were able to discontinue or reduce oral medications and five reported being able to return to work or school. No serious adverse events were reported. Conclusions Patients with POTS experienced significant functional improvement with reduction in autonomic symptoms following immunotherapy with SCIG or PLEX. This case series suggests that SCIG and PLEX may be safe and effective treatments for patients with severe POTS refractory to standard therapies. Randomized controlled trials are needed to determine the efficacy and safety of these long-term therapies.

Autonomic symptoms in migraine: Results of a prospective longitudinal study.

To assess the prevalence and burden of autonomic symptoms in migraine, and determine the relationship with migraine frequency. Autonomic symptoms in migraine have been theorized to occur in the setting of inter-ictal sympathetic hypoactivity and hyper-sensitivity. There is limited data prospectively assessing cranial and extra-cranial autonomic symptoms with a validated instrument, or longitudinal data on the relationship between migraine disease activity and autonomic symptoms. Patients attending a single tertiary academic center were recruited into a prospective cohort study between September 2020 and June 2022. In addition to standard clinical care, they completed several surveys including the Composite Autonomic Symptom Scale (COMPASS-31) questionnaire, a validated survey of autonomic symptoms. A total of 43 patients (66.7% female, median age 42, IQR 17) were included in the final analysis. There was a baseline 20 monthly headache days (MHD) (IQR 21.7), and 65.1% of the population had chronic migraine by ICHD-3 criteria. A significantly elevated weighted COMPASS-31 score was reported in 60.5% of respondents (mean 30.3, SD 13.3) at baseline. After 12 months treatment, significant improvements were reported in migraine frequency (median MHD 20-8.7) and disability (median Migraine Disability Assessment Score 67-48), but not in autonomic symptoms (mean score 30.3, SD 11.2). Autonomic symptoms were frequently reported in patients with migraine. However, they did not correlate with headache frequency or reversion to episodic frequency. Further study is required to elucidate specific approaches and treatments for autonomic symptoms, and further evaluate the underlying pathophysiological mechanisms.

Characterization of autonomic symptom burden in long COVID: A global survey of 2,314 adults.

Autonomic dysfunction is a known complication of post-acute sequelae of SARS-CoV-2 (PASC)/long COVID, however prevalence and severity are unknown. To assess the frequency, severity, and risk factors of autonomic dysfunction in PASC, and to determine whether severity of acute SARS-CoV-2 infection is associated with severity of autonomic dysfunction. Cross-sectional online survey of adults with PASC recruited through long COVID support groups between October 2020 and August 2021. 2,413 adults ages 18-64 years with PASC including patients who had a confirmed positive test for COVID-19 (test-confirmed) and participants who were diagnosed with COVID-19 based on clinical symptoms alone. The main outcome measure was the Composite Autonomic Symptom 31 (COMPASS-31) total score, used to assess global autonomic dysfunction. Test-confirmed hospitalized vs. test-confirmed non-hospitalized participants were compared to determine if the severity of acute SARS-CoV-2 infection was associated with the severity autonomic dysfunction. Sixty-six percent of PASC patients had a COMPASS-31 score >20, suggestive of moderate to severe autonomic dysfunction. COMPASS-31 scores did not differ between test-confirmed hospitalized and test-confirmed non-hospitalized participants [28.95 (15.62, 46.60) vs. 26.4 (13.75, 42.10); p = 0.06]. Evidence of moderate to severe autonomic dysfunction was seen in 66% of PASC patients in our study, independent of hospitalization status, suggesting that autonomic dysfunction is highly prevalent in the PASC population and independent of the severity of acute COVID-19 illness.