Mismatch between subjective and objective dysautonomia.

Autonomic symptom questionnaires are frequently used to assess dysautonomia. It is unknown whether subjective dysautonomia obtained from autonomic questionnaires correlates with objective dysautonomia measured by quantitative autonomic testing. The objective of our study was to determine correlations between subjective and objective measures of dysautonomia. This was a retrospective cross-sectional study conducted at Brigham and Women's Faulkner Hospital Autonomic Laboratory between 2017 and 2023 evaluating the patients who completed autonomic testing. Analyses included validated autonomic questionnaires [Survey of Autonomic Symptoms (SAS), Composite Autonomic Symptom Score 31 (Compass-31)] and standardized autonomic tests (Valsalva maneuver, deep breathing, sudomotor, and tilt test). The autonomic testing results were graded by a Quantitative scale for grading of cardiovascular reflexes, sudomotor tests and skin biopsies (QASAT), and Composite Autonomic Severity Score (CASS). Autonomic testing, QASAT, CASS, and SAS were obtained in 2627 patients, and Compass-31 in 564 patients. The correlation was strong between subjective instruments (SAS vs. Compass-31, r = 0.74, p < 0.001) and between objective instruments (QASAT vs. CASS, r = 0.81, p < 0.001). There were no correlations between SAS and QASAT nor between Compass-31 and CASS. There continued to be no correlations between subjective and objective instruments for selected diagnoses (post-acute sequelae of COVID-19, n = 61; postural tachycardia syndrome, 211; peripheral autonomic neuropathy, 463; myalgic encephalomyelitis/chronic fatigue syndrome, 95; preload failure, 120; post-treatment Lyme disease syndrome, 163; hypermobile Ehlers-Danlos syndrome, 213; neurogenic orthostatic hypotension, 86; diabetes type II, 71, mast cell activation syndrome, 172; hereditary alpha tryptasemia, 45). The lack of correlation between subjective and objective instruments highlights the limitations of the commonly used questionnaires with some patients overestimating and some underestimating true autonomic deficit. The diagnosis-independent subjective-objective mismatch further signifies the unmet need for reliable screening surveys. Patients who overestimate the symptom burden may represent a population with idiosyncratic autonomic-like symptomatology, which needs further study. At this time, the use of autonomic questionnaires as a replacement of autonomic testing cannot be recommended.

Network autonomic analysis of post-acute sequelae of COVID-19 and postural tachycardia syndrome.

BACKGROUND: The autonomic nervous system (ANS) is a complex network where sympathetic and parasympathetic domains interact inside and outside of the network. Correlation-based network analysis (NA) is a novel approach enabling the quantification of these interactions. The aim of this study is to assess the applicability of NA to assess relationships between autonomic, sensory, respiratory, cerebrovascular, and inflammatory markers on post-acute sequela of COVID-19 (PASC) and postural tachycardia syndrome (POTS). METHODS: In this retrospective study, datasets from PASC (n = 15), POTS (n = 15), and matched controls (n = 11) were analyzed. Networks were constructed from surveys (autonomic and sensory), autonomic tests (deep breathing, Valsalva maneuver, tilt, and sudomotor test) results using heart rate, blood pressure, cerebral blood flow velocity (CBFv), capnography, skin biopsies for assessment of small fiber neuropathy (SFN), and various inflammatory markers. Networks were characterized by clusters and centrality metrics. RESULTS: Standard analysis showed widespread abnormalities including reduced orthostatic CBFv in 100%/88% (PASC/POTS), SFN 77%/88%, mild-to-moderate dysautonomia 100%/100%, hypocapnia 87%/100%, and elevated inflammatory markers. NA showed different signatures for both disorders with centrality metrics of vascular and inflammatory variables playing prominent roles in differentiating PASC from POTS. CONCLUSIONS: NA is suitable for a relationship analysis between autonomic and nonautonomic components. Our preliminary analyses indicate that NA can expand the value of autonomic testing and provide new insight into the functioning of the ANS and related systems in complex disease processes such as PASC and POTS.

Multisystem Involvement in Post-Acute Sequelae of Coronavirus Disease 19.

OBJECTIVE: The purpose of this study was to describe cerebrovascular, neuropathic, and autonomic features of post-acute sequelae of coronavirus disease 2019 ((COVID-19) PASC). METHODS: This retrospective study evaluated consecutive patients with chronic fatigue, brain fog, and orthostatic intolerance consistent with PASC. Controls included patients with postural tachycardia syndrome (POTS) and healthy participants. Analyzed data included surveys and autonomic (Valsalva maneuver, deep breathing, sudomotor, and tilt tests), cerebrovascular (cerebral blood flow velocity [CBFv] monitoring in middle cerebral artery), respiratory (capnography monitoring), and neuropathic (skin biopsies for assessment of small fiber neuropathy) testing and inflammatory/autoimmune markers. RESULTS: Nine patients with PASC were evaluated 0.8 ± 0.3 years after a mild COVID-19 infection, and were treated as home observations. Autonomic, pain, brain fog, fatigue, and dyspnea surveys were abnormal in PASC and POTS (n = 10), compared with controls (n = 15). Tilt table test reproduced the majority of PASC symptoms. Orthostatic CBFv declined in PASC (-20.0 ± 13.4%) and POTS (-20.3 ± 15.1%), compared with controls (-3.0 ± 7.5%, p = 0.001) and was independent of end-tidal carbon dioxide in PASC, but caused by hyperventilation in POTS. Reduced orthostatic CBFv in PASC included both subjects without (n = 6) and with (n = 3) orthostatic tachycardia. Dysautonomia was frequent (100% in both PASC and POTS) but was milder in PASC (p = 0.002). PASC and POTS cohorts diverged in frequency of small fiber neuropathy (89% vs 60%) but not in inflammatory markers (67% vs 70%). Supine and orthostatic hypocapnia was observed in PASC. INTERPRETATION: PASC following mild COVID-19 infection is associated with multisystem involvement including: (1) cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction; (2) small fiber neuropathy and related dysautonomia; (3) respiratory dysregulation; and (4) chronic inflammation. ANN NEUROL 2022;91:367-379.