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Neurogenic orthostatic hypotension (nOH) is one of the most debilitating nonmotor symptoms in patients with Parkinson disease and other synucleinopathies. Patients with Parkinson disease and nOH suffer from more hospitalizations, emergency room visits, more telephone calls and e-mails to providers, and have a significantly shorter survival compared to patients with Parkinson disease and no nOH. Overall, health-related costs in patients with Parkinson disease and OH are 2.5-fold higher compared to patients with Parkinson disease without OH. Therefore, the development of effective therapies for patients with Parkinson disease and nOH should be a research priority. In recent years, better understanding of the pathophysiology of nOH has resulted in the identification of novel therapeutic targets and the development and approval of effective drug therapies, such as midodrine and droxidopa. We here review the design and endpoint selection for clinical trials of nOH in patients with Parkinson disease and other synucleinopathies, recapitulate the results of completed and ongoing clinical trials for nOH, and discuss common challenges and their potential remedies.
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A 10-year-old girl presented with ileus, urinary retention, dry mouth, lack of tears, fixed dilated pupils, and diffuse anhidrosis 7-days after a febrile illness. We hypothesized that her syndrome was due to autoimmunity against muscarinic acetylcholine receptors, blocking their activation. Using an indirect enzyme-linked immunosorbent assay for all five muscarinic receptors (M₁ -M₅ ) we identified in the patient's serum antibodies that selectively bound to M₃ receptors. In-vitro functional studies confirmed that these autoantibodies selectively blocked M₃ receptor activation. Thus, autoantibodies against M₃ acetylcholine receptors can cause acute postganglionic cholinergic dysautonomia. This article is protected by copyright. All rights reserved.

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: 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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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.

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.