Standardized Autonomic Testing in Patients With Probable Radiation-Induced Afferent Baroreflex Failure

Injury of the afferent limb of the baroreflex from neck radiation causes radiation-induced afferent baroreflex failure (R-ABF). Identification and management of R-ABF is challenging. We aimed to investigate the pattern of autonomic dysfunction on standardized autonomic testing in patients with probable R-ABF. We retrospectively analyzed all autonomic reflex screens performed at Mayo Clinic in Rochester, MN, between 2000 and 2020 in patients with probable R-ABF. Additional tests reviewed included ambulatory blood pressure monitoring, plasma norepinephrine, and thermoregulatory sweat test. We identified 90 patients with probable R-ABF. Median total composite autonomic severity score (range, 0–10) was 7 (interquartile range, 6–7). Cardiovascular adrenergic impairment was seen in 85 patients (94.4%), increased blood pressure recovery time after Valsalva maneuver in 71 patients (78.9%; median 17.4 seconds), and orthostatic hypotension in 68 patients (75.6%). Cardiovagal impairment was demonstrated by abnormal heart rate responses to deep breathing (79.5%), Valsalva ratio (87.2%), and vagal baroreflex sensitivity (57.9%). Plasma norepinephrine was elevated and rose appropriately upon standing (722–1207 pg/mL). Ambulatory blood pressure monitoring revealed hypertension, postural hypotension, hypertensive surges, tachycardia, and absence of nocturnal dipping. Blood pressure lability correlated with impaired vagal baroreflex function. Postganglionic sympathetic sudomotor function was normal in most cases; the most frequent thermoregulatory sweat test finding was focal neck anhidrosis (78.9%). Standardized autonomic testing in R-ABF demonstrates cardiovascular adrenergic impairment with orthostatic hypotension, blood pressure lability, and elevated plasma norepinephrine. Cardiovagal impairment is common, while sudomotor deficits are limited to direct radiation effects.

Evaluation and treatment of peripheral nervous system dysfunction in patients with prediabetes

The worldwide prevalence of prediabetes is steadily increasing, with up to a third of patients already showing signs of diabetic neuropathy (DN). Prediabetes includes impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or a combination of both.Recent diagnostic criteria of prediabetes according to Russian, European, and American clinical guidelines are presented. The review covers the most common forms of DN in patients with prediabetes (distal symmetric sensory polyneuropathy, painful DN, cardiovascular autonomic neuropathy) and their prevalence. Recommended methods of DN screening are discussed: diagnostic scales, sensory testing, nerve conduction study, autonomic testing, corneal confocal microscopy. The results of studies evaluating instrumental methods for diagnosing peripheral nervous system (PNS) dysfunction in prediabetes are discussed. Management tactics in patients with prediabetes and PNS dysfunction should include non-pharmacological and pharmacological interventions. Combining a low-calorie diet and regular physical activity can delay the development of diabetes mellitus and reduce the severity of neuropathic pain. In patients with painful DN, the first-line therapy includes pregabalin, gabapentin, and duloxetine. Since there is no current data on the effect of hypoglycemic therapy on the risks of development and/or progression of DN in patients with prediabetes, antioxidants are considered pathogenetic therapy. Alpha-lipoic acid (Berlition®) in the management of patients with prediabetes is discussed.

Abstract P207: Sleep Hygiene As An Intervention To Improve Autonomic Function

Introduction: Insufficient sleep is associated with increased heart rate (HR) and blood pressure (BP). Exaggerated cardiovascular reactivity to the cold pressor test (CPT) has been linked to an increased incidence of hypertension. This project investigates the effects of improved sleep hygiene on autonomic function at rest and in response to CPT. We hypothesize a decrease in BP and HR at rest, and attenuated BP and HR response during CPT. Methods: Fifty participants (59.8 ± 1.5 years; 31 women) completed 3 overnight in-hospital stays in which they had continuous ECG and beat-to-beat BP monitoring. The first stay (S1) was a baseline control; the second stay (S2) was a 4-week wait-list control; the third stay (S3) followed an 8-week randomly assigned intervention that used sleep hygiene approaches along with scheduling to either A) stabilize sleep timing, or B) stabilize and extend the bed period. This study is still ongoing, so we are blind to the specific arm that the participants were randomized to. During each stay, autonomic testing was performed about four hours after the participant awoke, including a 5-minute resting period where breathing was controlled (BL), a 3-minute resting period where breathing was not controlled (CPT BL), and 2-minute CPT when participants then submerged their hand in 3°C water. Linear mixed models analyzing the changes in HR and systolic BP (SBP) across the three stays were used. Results: During the 5-minute BL, HR did not significantly decrease from S1 to S2 (p=.310) but did significantly decrease by 2 bpm from S2 to S3 (p=.006). SBP decreased by 7 mmHg from S1 to S2 (p=.022) but did not significantly decrease from S2 to S3 (p=.907). During CPT in all stays, HR and SBP significantly increased compared to CPT BL (p<0.05). There was a significant stay x test interaction effect in HR (interaction, p=.042), but not in SBP (interaction p=.361). Conclusion: While we are still blind to condition, both arms actively improve sleep hygiene. These preliminary data suggest that stabilization of sleep timing and possibly duration, has a positive impact on autonomic function as seen through the decreases in HR at rest and during CPT.

Cutaneous Alpha-Synuclein is Correlated with Autonomic Impairment in Isolated REM Sleep Behavior Disorder

Study Objectives To define the clinical implications of cutaneous phosphorylated α-synuclein (p-syn) and its association with subjective and objective measures of autonomic impairment and clinical features including antidepressant use in isolated REM sleep behavior disorder (iRBD). Methods Twenty-five iRBD patients had quantified neurological and cognitive examinations, olfactory testing, questionnaires, autonomic function testing, and 3 punch skin biopsies (distal thigh, proximal thigh, neck). Skin biopsies were stained for the pan-axonal marker PGP 9.5 and co-stained with p-syn, and results were compared to 28 patients with Parkinson’s disease (PD) and 18 healthy controls. Equal numbers of iRBD patients on and off antidepressants were recruited. The composite autonomic severity scale (CASS) was calculated for all patients. Results P-syn was detected in 16/25 (64%) of iRBD patients, compared to 27/28 (96%) of PD and 0/18 controls. The presence of p-syn at any biopsy site was correlated with both sympathetic (CASS adrenergic r = 0.6, p &lt; 0.05) and total autonomic impairment (CASS total r = 0.6, p &lt; 0.05) on autonomic reflex testing in iRBD patients. These results were independent of the density of p-syn at each site. There was no correlation between p-syn and antidepressant use. Conclusions In patients with iRBD, the presence of cutaneous p-syn was detected in most patients and was associated with greater autonomic dysfunction on testing. Longitudinal follow-up will aid in defining the predictive role of both skin biopsy and autonomic testing in determining phenoconversion rates and future disease status.

COVID-19 Dysautonomia

Objective: To report a case series of dysautonomia associated with COVID-19 infection.Methods: This is a retrospective review of patients evaluated in the autonomic clinic at our institution with suspected signs and symptoms of dysautonomia who underwent formal evaluation, including autonomic testing.Results: Six patients were identified with signs and symptoms suggestive of dysautonomia who underwent autonomic testing. All patients had symptoms typical of COVID-19 infection, though none were hospitalized for these or other symptoms. All patients reported symptoms of postural lightheadedness and near-syncope, fatigue, and activity intolerance. Five patients reported the onset of autonomic symptoms concomitant with other COVID-19 symptoms, with the other patient reporting symptom onset 6 weeks following initial COVID-19 symptoms. Autonomic testing demonstrated an excessive postural tachycardia in 4 patients, a hypertensive response with head-up tilt in 3 patients, orthostatic hypotension in 1 patient, and sudomotor impairment in 1 of the patients with excessive postural tachycardia.Conclusions: We present clinical features and results of autonomic testing in 6 patients with a history COVID-19 infection. While all patients reported typical features of orthostatic intolerance, fatigue, and activity intolerance, the results of autonomic testing were heterogenous, with orthostatic hypotension in 1 patient, excessive postural tachycardia typical of postural tachycardia syndrome in 4 patients, and postural hypertension in 3 patients.

Sympathetic and sensory nerve fiber function in multiple system atrophy and idiopathic Parkinson’s disease

Objective To explore small fiber somatosensory and sympathetic function in PD and MSA. Methods We recruited 20 PD patients (7 women, median age 65.5 years; IQR 54.75–70.0), 10 MSA patients (4 women; median age 68 years; IQR 66.25–74.0), and 10 healthy subjects (HC; 4 women, median age 68; IQR 59.0–71.0 years). Autonomic testing included forehead cooling, intradermal microdialysis of norepinephrine (NE; 10–5; 10–6; 10–7; and 10–8), and orthostatic hypotension (OH); somatosensory testing included quantitative sensory testing (QST) according to the protocol of the German Research Network on Neuropathic Pain (DFNS). Results OH occurred more frequently in PD (p = 0.018) and MSA (p = 0.002) compared to HC. Vasoconstriction responses were stronger in PD compared to MSA during forehead cooling (p = 0.044) and microdialysis of physiologically concentrated NE solutions (10–7; 10–8; p = 0.017). PD and MSA had impaired cold (PD: p < 0.01; MSA: p < 0.05) and warm detection thresholds (PD and MSA, both p < 0.05). The mechanical detection threshold was higher in PD (p < 0.01). Conversely, mechanical pain thresholds were decreased in PD and MSA (both p < 0.001), indicating mechanical hyperalgesia. Conclusion In contrast to MSA, we found evidence of peripheral adrenoreceptor hypersensitivity in PD, probably caused by peripheral sympathetic denervation. Sensory testing revealed peripheral neuropathy and central pain sensitization in PD and MSA. Jointly, our data demonstrate autonomic and somatosensory dysfunction in PD and MSA.

Fatigue following COVID-19 infection is not associated with autonomic dysfunction

Background The long-term clinical and physiological consequences of COVID-19 infection remain unclear. While fatigue has emerged as a common symptom following infection, little is known about its links with autonomic dysfunction. SARS-CoV-2 is known to infect endothelial cells in acute infection, resulting in autonomic dysfunction. Here we set out to test the hypothesis that this results in persistent autonomic dysfunction and is associated with post-COVID fatigue in convalescent patients. Methods We recruited 20 fatigued and 20 non-fatigued post-COVID patients (median age 44.5 years, 36/40 (90%) female, median time to follow up 166.5 days). Fatigue was assessed using the Chalder Fatigue Scale. These underwent the Ewing’s autonomic function test battery, including deep breathing, active standing, Valsalva manoeuvre and cold-pressor testing, with continuous electrocardiogram and blood pressure monitoring, as well as near-infrared spectroscopy-based cerebral oxygenation. 24-hour ambulatory blood pressure monitoring was also conducted, and patients completed the generalised anxiety disorder-7 questionnaire. We assessed between-group differences in autonomic function test results and used unadjusted and adjusted linear regression to investigate the relationship between fatigue, anxiety, and autonomic test results. Results We found no pathological differences between fatigued and non-fatigued patients on autonomic testing or on 24-hour blood pressure monitoring. Symptoms of orthostatic intolerance were reported by 70% of the fatigued cohort at the time of active standing, with no associated physiological abnormality detected. Fatigue was strongly associated with increased anxiety (p <0.001), with no patients having a pre-existing diagnosis of anxiety. Conclusions These results demonstrate the significant burden of fatigue, symptoms of autonomic dysfunction and anxiety in the aftermath of COVID-19 infection, but reassuringly do not demonstrate pathological findings on autonomic testing.

“Complex” Vasovagal Syncope: A Zebra Among Horses

Background: Vasovagal syncope (VVS) occurs due to cerebral hypoperfusion from a fall in blood pressure, with accompanying bradycardia in most cases. Seizure and/or asystole may accompany VVS, though their prediction within the VVS cohort remains elusive.Objective: To further characterize VVS and to find predictive features of “complex” VVS (defined as VVS associated with seizures and/or asystole).Methods: We reviewed medical records of all patients who were referred for orthostatic intolerance and had a definite VVS during the head-up tilt table testing (HUTT). The following variables were recorded: cardiovascular indices during HUTT, autonomic testing results, and semiology of asystole and/or seizure when present. Simple frequency and correlation analysis were performed using the ANOVA.Results: A total of 78 independent VVS were recorded in 60 patients of which 24% were not preceded by presyncope. Vasodepressor (45%) and mixed (38%) VVS were the most prevalent types. Eighteen (23%) were complex VVS; five had an associated seizure (SySz), nine were accompanied by asystole (SyAs), and four had both (SySzAs). Males were significantly more likely to have complex VVS. Mean asystole duration was somewhat longer in the SyAsSz group. The severity of bradycardia significantly correlated with complex VVS and was a predictor of SySz. Autonomic abnormalities were frequent but did not distinguish the two VVS subgroups. Seizures had multiple distinguishing features from those typically associated with epileptic seizures.Conclusions: The underlying pathophysiologic mechanisms of complex VVS remain unclear, but the severity of cerebral hypoperfusion due to bradycardia likely plays a key role in seizure generation.