Faculty Bibliography

BACKGROUND:Despite innovations in left ventricular assist devices (LVAD) technology, stroke remains a leading cause of morbidity and mortality in this population. Major clinical trials of LVAD have used various definitions and approaches to measuring stroke outcomes which may limit comparison of stroke risk between different devices. METHODS:Data from the five major LVAD randomized, controlled, trials was abstracted to compare definitions of stroke (composite, ischemic, hemorrhagic and disabling) and stroke event rates across trials. Methodological limitations and suggestions to improve research and clinical practices for stroke and LVAD were identified. RESULTS:Comparison of stroke events across LVAD clinical trials is confounded by methodological variability including heterogeneity in stroke definitions, non-standardized evaluation of stroke etiology, oversimplification of stroke severity classification, and inconsistent event rate reporting due to data censoring at the time of death or transplant. Variability in the study of stroke in LVAD patients limits the ability to compare devices and design prevention strategies to mitigate stroke risk. CONCLUSIONS:Based on this review, we propose that future clinical trials: 1) utilize standardized stroke definitions and define stroke subtypes, 2) ensure that neurologists are integrated in study design and event adjudication, 3) include more thorough evaluations of stroke etiology using multimodality techniques, and 4) adopt the National Institutes of Health Stroke Scale to define stroke severity.

Von Economo neurons (VENs) and fork cells are principally located in the anterior cingulate cortex (ACC) and the frontoinsular cortex (FI). Both of these regions integrate inputs from the autonomic nervous system (ANS) and are involved in decision-making and perception of the emotional states of self and others. Familial dysautonomia (FD) is an orphan disorder characterized by autonomic dysfunction and behavioral abnormalities including repetitive behavior and emotional rigidity, which are also seen in autism spectrum disorder. To understand a possible link between the ANS and the cortical regions implicated in emotion regulation we studied VENs and fork cells in an autonomic disorder. We determined the densities of VENs, fork cells, and pyramidal neurons and the ratio of VENs and fork cells to pyramidal neurons in ACC and FI in 4 FD patient and 6 matched control brains using a stereologic approach. We identified alterations in densities of VENs and pyramidal neurons and their distributions in the ACC and FI in FD brains. These data suggest that alterations in migration and numbers of VENs may be involved in FD pathophysiology thereby supporting the notion of a functional link between VENs, the ANS and the peripheral nervous system in general.

Background/UNASSIGNED:In the current consensus diagnostic criteria, the diagnosis of probable multiple system atrophy (MSA) is based solely on clinical findings, whereas neuroimaging findings are listed as aid for the diagnosis of possible MSA. There are overlapping phenotypes between MSA-parkinsonian type and Parkinson's disease, progressive supranuclear palsy, and dementia with Lewy bodies, and between MSA-cerebellar type and sporadic adult-onset ataxia resulting in a significant diagnostic delay and misdiagnosis of MSA during life. Objectives/UNASSIGNED:In light of an ongoing effort to revise the current consensus criteria for MSA, the Movement Disorders Society Multiple System Atrophy Study Group performed a systematic review of original articles published before August 2019. Methods/UNASSIGNED:We included articles that studied at least 10 patients with MSA as well as participants with another disorder or control group for comparison purposes. MSA was defined by neuropathological confirmation, or as clinically probable, or clinically probable plus possible according to consensus diagnostic criteria. Results/UNASSIGNED:We discuss the pitfalls and benefits of each diagnostic test and provide specific recommendations on how to evaluate patients in whom MSA is suspected. Conclusions/UNASSIGNED:This systematic review of relevant studies indicates that imaging and autonomic function tests significantly contribute to increasing the accuracy of a diagnosis of MSA.

Background: Inadequate norepinephrine (NE) release in neurogenic orthostatic hypotension (nOH) causes blood pressure to fall on standing and debilitating symptoms of cerebral hypoperfusion. Ampreloxetine, a novel, long-acting NE reuptake inhibitor, potentiates the effects of endogenous NE, and may improve symptoms of nOH. The objective of the study was to explore the durability of effect and safety of once-daily oral ampreloxetine for the symptomatic treatment of nOH in subjects with synucleinopathies.
Method(s): In an open-label, phase 2, exploratory, multicenter study, subjects received open-label ampreloxetine (3-20 mg) 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 and Orthostatic Hypotension Daily Activities Scale (OHDAS) composite scores, and Patient Global Impression of Severity (PGI-S).
Result(s): Seventeen symptomatic subjects (baseline OHSA#1 score >4) were enrolled (mean age, 65 years). At Week 4, mean (SD) improvement on OHSA#1 was -3.8 (3.1) points; approximately 77% of subjects reported >=1-point improvement (minimal clinically important difference). At Week 20, mean improvement was -3.1 (3.0) points; approximately 86% reported >=1-point improvement. Symptom improvement was observed as early as Week 1 and was sustained throughout the study. Deterioration to baseline symptom severity was after ampreloxetine withdrawal. Similar trends were seen in OHSA and OHDAS composite scores, and PGI-S. Most common adverse events were urinary tract infection (24%), hypertension (19%), and headache (14%), with no study-drug related serious adverse events.
Conclusion(s): Ampreloxetine showed durable symptom improvement in symptomatic subjects with nOH over 20 weeks, with return to baseline symptom severity after ampreloxetine withdrawal. Ampreloxetine was well tolerated with a favorable safety profile. These encouraging open-label findings are being evaluated further in ongoing Phase 3, double-blind, confirmatory studies in subjects with nOH and synucleinopathies.
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Head and neck tumors can affect afferent baroreceptor neurons and either interrupt or intermittently increase their signaling, causing blood pressure to become erratic. When the afferent fibers of the baroreflex are injured by surgery or radiotherapy or fail to develop as in familial dysautonomia, their sensory information is no longer present to regulate arterial blood pressure, resulting in afferent baroreflex failure. When the baroreflex afferents are abnormally activated, such as by paragangliomas in the neck, presumably by direct compression, they trigger acute hypotension and bradycardia and frequently syncope, by a mechanism similar to the carotid sinus syndrome. We describe our observations in a large series of 23 patients with afferent baroreflex dysfunction and the cardiovascular autonomic features that arise when the sensory baroreceptor neurons are injured or compressed. The management of afferent baroreceptor dysfunction is limited, but pharmacological strategies can mitigate blood pressure swings, improve symptoms, and may reduce hypertensive organ damage. Although rare, the prevalence of afferent baroreflex dysfunction appears to be increasing in middle-aged men due to human papillomavirus related oropharyngeal cancer.

Neurogenic orthostatic hypotension (nOH) is among the most debilitating nonmotor features of patients with Parkinson's disease (PD) and other synucleinopathies. Patients with PD and nOH generate more hospitalizations, make more emergency room visits, create more telephone calls/mails to doctors, and have earlier mortality than those with PD but without nOH. Overall, the health-related cost in patients with PD and OH is 2.5-fold higher compared with patients with PD without OH. Hence, developing effective therapies for nOH should be a research priority. In the last few decades, improved understanding of the pathophysiology of nOH has led to the identification of therapeutic targets and the development and approval of two drugs, midodrine and droxidopa. More effective and safer therapies, however, are still needed, particularly agents that could selectively increase blood pressure only in the standing position because supine hypertension is the main limitation of available drugs. Here we review the design and conduct of nOH clinical trials in patients with PD and other synucleinopathies, summarize the results of the most recently completed and ongoing trials, and discuss challenges, bottlenecks, and potential remedies.

Acute-onset and severe sensory and autonomic deficits with no motor dysfunction, typically preceded by a febrile illness, with poor recovery, and often fatal outcome are the hallmark features of acute sensory and autonomic neuronopathy (ASANN). Pathologically and electrophysiologically, ASANN is characterized by an extensive ganglionopathy affecting sensory and autonomic ganglia with preservation of motor neurons. Consequently, patients, usually children or young adult, develop acute-onset profound widespread loss of all sensory modalities resulting in automutilations, as well as autonomic failure causing neurogenic orthostatic hypotension, neurogenic underactive bladder, and gastroparesis and constipation. The diagnosis is clinical with support of nerve conduction studies and autonomic testing, as well as spinal cord magnetic resonance imaging showing characteristic posterior cord hyperintensities. Although the presumed etiology is immune-mediated, further studies are required to clarify the physiopathology of the disease. We here performed a systematic review of the epidemiology, pathophysiology, diagnosis, and management of ASANN, with three representative cases that recently presented at our clinic. All three patients had the typical clinical manifestations of ASANN but in different combinations, illustrating the variable phenotype of the disorder. Immunosuppression is seldom effective. Management options are limited to supportive and symptomatic care with the goal of minimizing complications and preventing death.

Background: To assess acute clinical effects and safety of single-dose oral ampreloxetine, a novel, long-acting, selective norepinephrine reuptake inhibitor in subjects with neurogenic orthostatic hypotension (nOH).
Method(s): In a 5-day dosing study, subjects received placebo on Day 1, followed by ascending doses of ampreloxetine (range:1-20 mg). A subset of subjects were randomized to placebo or ampreloxetine in a 1-day double-blind study. Assessments included change in seated and standing systolic blood pressure (SBP), and Orthostatic Hypotension Symptom Assessment-Item 1 (OHSA#1; dizziness, lightheadedness, feeling faint).
Result(s): Of 34 subjects (mean age, 66 years), 15 and 13 subjects received ampreloxetine 10 and 20 mg, respectively, as maximum tolerated dose. Ampreloxetine 10 mg showed the most consistent response for increase in seated SBP relative to placebo (mean [SD] change in seated SBP 4.9 [20.1] mmHg more than placebo 4 hours post-dose). In the double-blind study (ampreloxetine, n=5 [median dose, 10 mg]; placebo, n=5), relative to placebo, for the ampreloxetine treatment group, increase in seated (mean difference from placebo, 29.9 mmHg at 4 hours post-dose; p < 0.05) and 3-minute standing SBP (mean difference, 35.0 mmHg at 4 hours post-dose) was more pronounced for the ampreloxetine treatment group to 9 hours and 10 hours post-dose, respectively, and 3-minute standing SBP was more pronounced for subjects randomized to ampreloxetine up to 10 hours post-dose. Twice as many subjects in the ampreloxetine treatment arm reported symptom improvement on OHSA#1. Most common adverse events were headache and urinary tract infection, with no serious events.
Conclusion(s): In subjects with nOH, 10 mg ampreloxetine produced a consistent increase in seated SBP relative to placebo. Compared to placebo, ampreloxetine showed greater increase in seated and standing SBP up to 10 hours post-dose, and greater symptom improvement. Ampreloxetine was well tolerated. These results support assessment of longer-term effects of ampreloxetine in nOH.
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Background: In neurogenic orthostatic hypotension (nOH), blood pressure (BP) falls due to inadequate norepinephrine (NE) release when upright. Ampreloxetine, a novel, long-acting NE reuptake inhibitor, potentiates effects of endogenous NE and has shown durable symptom improvement in subjects with nOH associated with synucleinopathies. The objective of this study was to evaluate measures of BP regulation in subjects with symptomatic nOH treated with open-label ampreloxetine.
Method(s): In a phase 2, multicenter, exploratory study, subjects received ampreloxetine once-daily (3-20 mg) for up to 20 weeks, with 4-week follow-up after ampreloxetine withdrawal and restarting other pressor agents. Assessments included Orthostatic Hypotension Symptom Assessment Item 1 score (OHSA#1; dizziness, lightheadedness, feeling faint); standing, sitting, and supine systolic BP (SBP); standing duration; and plasma NE.
Result(s): Seventeen symptomatic subjects (baseline OHSA#1 score >4) were enrolled (mean age, 65 years). Standing and sitting SBP, standing duration, plasma NE, and symptoms improved from Weeks 1 to 20. Mean increase in 3-minute standing SBP from baseline was 9.0 mmHg at Week 4 and 10.8 mmHg at Week 20; >50% of subjects maintained SBP >80 mmHg. 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 (1664.93-2231.67 pmol/l). After ampreloxetine withdrawal and restarting other pressor agents, standing SBP remained increased; however, nOH symptoms deteriorated to baseline. Ampreloxetine was well tolerated.
Conclusion(s): Ampreloxetine has previously demonstrated durable symptom improvement in nOH. Symptom improvement was accompanied by increase in standing and sitting SBP, standing duration, and NE plasma levels, with little effect on supine SBP. These encouraging findings are being evaluated further in ongoing Phase 3, double-blind, confirmatory studies in subjects with nOH and synucleinopathies.
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