Faculty Bibliography

Background and aims: Distinguishing neurogenic orthostatic hypotension (nOH) from other causes of blood pressure (BP) instability is of pivotal importance in clinical practice. Norcliffe-Kaufmann et al. recently showed that when the ratio between the heart rate increase and the systolic BP fall after 3 minutes of passive head-up tilt (HUT) is <0.492, this indicates nOH. Here we aimed at validating this nOH ratio with standard arm-cuff BP measurements upon active standing (AS).
Method(s): We screened all patients who had undergone cardiovascular autonomic function testing at the Innsbruck Medical University between January 2008 and September 2019.
Result(s): We included 51 patients (27 with Parkinson's disease, 22 with multiple system atrophy) diagnosed with orthostatic hypotension either upon AS or HUT. 49 patients showed no BP overshoot after the Valsalva maneuver and were thus classified as having nOH. Out of these, 27 patients showed a systolic BP fall >=20mmHg in both the HUT and the AS and were considered for further analysis. The nOH ratio was <0.492 for 20 patients during HUT and for 19 patients during the AS. The sensitivity of the nOH ratio for neurogenic OH was therefore 74% upon HUT and 70% upon AS. The correlation between the nOH-ratio upon HUT and AS was strong (rho=0.86, p<0.001).
Conclusion(s): A nOH ratio <0.492 evaluated with standard arm-cuff heart rate and BP measurements has a good sensitivity for nOH both upon HUT and AS. This ratio can be therefore used as bedside nOH screening measure, if no tilt-test facilities are available

Background and aims: In neurogenic orthostatic hypotension (nOH), standing blood pressure (BP) falls due to inadequate norepinephrine (NE) release. Ampreloxetine, a novel, long-acting, NE reuptake inhibitor, has shown durable symptom improvement in subjects with nOH associated with synucleinopathies. The objective of this study was to evaluate BP regulation in subjects with symptomatic nOH treated with open-label ampreloxetine.
Method(s): In a phase 2 study, subjects received ampreloxetine once-daily (3-20mg) for up to 20 weeks, with 4-week follow-up after ampreloxetine withdrawal. Assessments included Orthostatic Hypotension Symptom Assessment Item 1 score (OHSA#1; dizziness, lightheadedness, feeling faint); standing/sitting/supine systolic BP (SBP); standing duration; and plasma NE.
Result(s): 17 symptomatic subjects (baseline OHSA#1 score >4) were enrolled (mean age, 65 years). Mean increase in 3-minute standing SBP from baseline at Weeks 4 and 20 was 9.0mmHg and 10.8mmHg, respectively; >50% of subjects maintained SBP >80mmHg. Sitting SBP changes were less, with little change in supine SBP. At Week 4, 67% of subjects could stand for >5 mins, 31% improvement from baseline. NE plasma levels rose from pre-dose to Week 4 (1664.93-2231.67pmol/l). Baseline NE plasma levels correlated with standing BP increase. Ampreloxetine was well tolerated. Durable symptom improvement in nOH was accompanied by increase in standing and sitting SBP, standing duration, and NE plasma levels, with little effect on supine SBP.
Conclusion(s): These encouraging findings on BP regulation in nOH with ampreloxetine treatment for up to 5 months are being evaluated in ongoing Phase 3, double-blind, confirmatory studies in subjects with nOH

Background and aims: Dementia is considered a nonsupportive diagnostic feature for multiple system atrophy (MSA). Nevertheless, post-mortem verified dementia with Lewy bodies and Parkinson's disease masquerade as MSA. Cognitive impairment (CI), especially executive dysfunction, may occur in MSA patients. It is, however, unclear whether CI manifests in early disease stages.
Objective(s): To compare the prevalence of CI in MSA versus other Lewy Body disorders (LBD), including dementia with Lewy bodies and Parkinson's disease, in early (<3 years from symptom onset) versus more advanced disease stages (>=3 years from symptom onset).
Method(s): A total of 364 patients (LBD: n=83; MSA: n=281) of the natural history study of synucleinopathies register have been analysed. Consensus diagnostic criteria for dementia with Lewy bodies, Parkinson's disease and MSA were applied. To assess CI, the Montreal Cognitive Assessment (MoCA) has been used.
Result(s): In early disease stages, median MoCA scores did not differ significantly between MSA and LBD. In advanced disease stages, MSA patients had a significantly higher median MoCA score compared to LBD patients (27 versus 25, p=0.006). Comparison of the median MoCA Scores of LBD versus MSA patients at early and advanced disease stages
Conclusion(s): In patients with longer disease duration severity of CI helps to differentiate LBD from MSA

Background and aims: Inadequate norepinephrine (NE) release in neurogenic orthostatic hypotension (nOH) causes fall in standing blood pressure. Ampreloxetine, a novel, long-acting NE reuptake inhibitor may improve symptoms of nOH. The objective of this study was to explore durability of effect and safety of once-daily oral ampreloxetine for symptomatic treatment of nOH.
Method(s): In an open-label, phase 2, exploratory study, subjects received ampreloxetine (3-20mg) once-daily for up to 20 weeks, with 4-week follow-up after ampreloxetine withdrawal and restarting alternative pressor agents. Assessments included Orthostatic Hypotension Symptom Assessment Item 1 (OHSA#1; dizziness, lightheadedness, feeling faint), OHSA/Orthostatic Hypotension Daily Activities Scale (OHDAS) composite scores, and change in Patient Global Impression of Severity (PGI-S).
Result(s): Seventeen symptomatic subjects (baseline OHSA#1 score >4) were enrolled (mean age, 65 years). At Weeks 4 and 20, mean (SD) improvement on OHSA#1 was -3.8 (3.1) and -3.1 (3.0) point, and ~77% and ~86% of subjects reported >=1-point improvement, respectively. Improvement, seen as early as Week 1, was sustained throughout the study. Deterioration to baseline severity was observed after ampreloxetine withdrawal. Similar trends were seen in OHSA/OHDAS composite scores, and change in PGI-S. Most common adverse events (AEs) were urinary tract infection (24%), hypertension (19%) and headache (14%), with no study-drug-related serious AEs. Ampreloxetine showed durable symptom improvement over 20 weeks, with return to baseline severity after ampreloxetine withdrawal. Ampreloxetine was well tolerated.
Conclusion(s): These encouraging findings of durable symptom improvement with open-label ampreloxetine treatment are being evaluated in ongoing Phase 3, doubleblind, confirmatory studies in subjects with nOH