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.

PURPOSE/OBJECTIVE:To assess the relationship between depressive symptoms and self-perceived severity of autonomic dysfunction in patients with multiple system atrophy (MSA). METHODS:Cross-sectional evaluation of patients with MSA who underwent autonomic testing, Unified MSA Rating Scale (UMSARS)-1 and -2, rating of the presence and severity of depressive symptoms (Zung scale), quality of life (SF-36), body vigilance, anxiety (Spielberger's anxiety scale), severity of autonomic dysfunction with the Composite Autonomic Symptoms Score (COMPASS-31), and severity of orthostatic hypotension (OH) symptoms with the Orthostatic Hypotension Questionnaire (OHQ). RESULTS:Fifty-eight patients (32 women) with probable MSA (aged 61.8 ± 8.6 years; disease duration 4.3 ± 2.1 years) were studied. Forty patients (69%) had symptoms of depression in the Zung scale. Age, disease duration, and motor disability were similar in those with and without symptoms of depression. Despite a similar orthostatic blood pressure fall, the severity of orthostatic symptoms was higher in patients with symptoms of depression (p = 0.004). Depression scores were associated with higher burden of autonomic symptoms (R = 0.401, p = 0.02), specifically with the COMPASS-31 items related to orthostatic intolerance (R = 0.337, p = 0.045), and with the OHQ (R = 0.529; p < 0.001). A multivariable regression model including age, sex, UMSARS, and drop in systolic blood pressure upon head-up tilt as covariates showed that the burden of depressive symptoms was independently associated with the OHQ score: for every 1-unit increase in the Zung depression score, there was a 1.181-point increase in the total OHQ score. CONCLUSIONS:In patients with MSA, depressive symptoms worsen the perceived severity of autonomic symptoms in general and orthostatic hypotension in particular. Our findings have implications for clinical trial design.

PURPOSE/OBJECTIVE:The primary objective of this study was to examine the relationship of longitudinal changes in autonomic symptom burden and longitudinal changes in activities of daily living (ADLs); a secondary analysis examined the impact of depressive symptoms in this relationship. METHODS:Data were retrieved from the Parkinson's Progression Markers Initiative (PPMI), a dataset documenting the natural history of newly diagnosed Parkinson's disease (PD). The analysis focused on data from baseline, visit 6 (24 months after enrollment), and visit 12 (60 months after enrollment). The impact of longitudinal changes in autonomic symptom burden on longitudinal changes in ADLs function was examined. A secondary mediation analysis was performed to investigate whether longitudinal changes in depressive symptoms mediate the relationship between longitudinal changes in autonomic symptom burden and ADLs function. RESULTS:Changes in autonomic symptom burden, cognitive function, depressive symptoms, and motor function all correlated with ADLs. Only changes in ADLs and depression were found to be associated with changes in autonomic symptom burden. We found that longitudinal change in autonomic symptoms was a significant predictor of change in ADLs at 24 and 60 months after enrollment, with the cardiovascular subscore being a major driver of this association. Mediation analysis revealed that the association between autonomic symptoms and ADLs is partially mediated by depressive symptoms. CONCLUSIONS:Longitudinal changes in autonomic symptoms impact ADLs function in patients with early signs of PD, both directly and indirectly through their impact on depressive symptoms. Future investigation into the influence of treatment of these symptoms on outcomes in PD is warranted.

PURPOSE OF REVIEW/OBJECTIVE:This article reviews the management of orthostatic hypotension with emphasis on neurogenic orthostatic hypotension. RECENT FINDINGS/RESULTS:Establishing whether the cause of orthostatic hypotension is a pathologic lesion in sympathetic neurons (ie, neurogenic orthostatic hypotension) or secondary to other medical causes (ie, non-neurogenic orthostatic hypotension) can be achieved by measuring blood pressure and heart rate at the bedside. Whereas fludrocortisone has been extensively used as first-line treatment in the past, it is associated with adverse events including renal and cardiac failure and increased risk of all-cause hospitalization. Distinguishing whether neurogenic orthostatic hypotension is caused by central or peripheral dysfunction has therapeutic implications. Patients with peripheral sympathetic denervation respond better to norepinephrine agonists/precursors such as droxidopa, whereas patients with central autonomic dysfunction respond better to norepinephrine reuptake inhibitors. SUMMARY/CONCLUSIONS:Management of orthostatic hypotension is aimed at improving quality of life and reducing symptoms rather than at normalizing blood pressure. Nonpharmacologic measures are the key to success. Pharmacologic options include volume expansion with fludrocortisone and sympathetic enhancement with midodrine, droxidopa, and norepinephrine reuptake inhibitors. Neurogenic supine hypertension complicates management of orthostatic hypotension and is primarily ameliorated by avoiding the supine position and sleeping with the head of the bed elevated.

Orthostatic hypotension (OH) is a sustained fall in blood pressure on standing that can cause symptoms of organ hypoperfusion. OH is associated with increased morbidity and mortality and leads to a significant number of hospital admissions. OH can be caused by volume depletion, blood loss, cardiac pump failure, large varicose veins, medications, or defective activation of sympathetic nerves and reduced norepinephrine release upon standing. Neurogenic OH is a frequent and disabling problem in patients with synucleinopathies such as Parkinson disease, multiple system atrophy, and pure autonomic failure, and it is commonly associated with supine hypertension. Several therapeutic options are available.

Objective: To describe an unusual case of a young girl of Jewish Ashkenazi descent with two rare genetic disorders: familial dysautonomia and congenital adrenal hyperplasia.
Method(s): Case report.
Result(s): Female patient presenting with hypotonia, failure to thrive, recurrent vomiting and frequent lower respiratory tract infections during the first year of life. Her physical exam disclosed genital ambiguity and, because an older sister had a diagnosis of congenital adrenal hyperplasia, the diagnosis was suspected in this case, and confirmed by low levels of cortisol and aldosterone. Targeted genetic testing showed homozygosis for a pathogenic variant in the CYP21A2 gene (c.293-13C[G, aka I2G, well-described in Jewish Ashkenazi patients) and heterozygosis for 7 other variants in the same gene. She was started on fludrocortisone for mineralocorticoid replacement therapy. Additional signs and symptoms were identified including frequent aspiration pneumonias prompting a gastrostomy tube placement at 6 months of age, emotionally-induced episodes of face, hand and feet blotching, frequent falls, impaired sensitivity to pain, and lack of tears. Additional genetic testing at age 2 disclosed homozygous copies of the founder mutation variant of familial dysautonomia (variant IVS20?6 T[C) in the IKBKAP gene.
Conclusion(s): The presence of one rare genetic disorder does not preclude the presence of another rare genetic disorder. Signs and symptoms not consistent with one diagnosed genetic disorder should prompt suspicion of additional causes

Background: Disease progression of multiple system atrophy (MSA) as measured by the Unified Multiple System Atrophy Rating Scale (UMSARS) varied significantly in natural history studies. Reported 1-year UMSARS-1 and UMSARS-2 progression rates ranged from 3.9 to 6.5 and 3.5 to 8.2, respectively. We hypothesize that this variability is due, at least in part, to differences in severity at enrollment and a potential ceiling effect in the scale, so that patients in more advanced stages may appear to worsen less, which would have important implications for clinical trial design.
Method(s): We analyzed the rate of change in the UMSARS in a large international cohort of well-characterized patients with a clinical diagnosis of possible or probable MSA enrolled in the Natural History Study of Synucleinopathies. Annualized progression rates were obtained using 2-year follow-up data.
Result(s): 293 patients (62.0+/-7.8 years old) with MSA were enrolled. Disease duration was 4.5+/-3.6 years. 98 patients completed 1-year evaluations and 48 completed the 2-year evaluation. The 12-month progression rates were 5.5+/-5.3 for the UMSARS-I, 6.6+/-5.2 for the UMSARS-II, and 11.9+/-9.8 for the total score. The 24-month progression rates were 10.8+/-7.1 for the UMSARS-I, 12.5+/-7.9 for the UMSARS-II, and 22.6+/-13.7 for the total score. Annualized progression rates were divided according to their baseline UMSARS-I and UMSARS II. There was a significant (p=0.0461) inverse relationship between rate of progression and UMSARS-I at baseline. A similar, but not significant trend was observed with UMSARS-II at baseline.
Conclusion(s): The rate of progression as measured by UMSARS is influenced by the baseline disease severity. A ceiling effect should be considered when planning enrollment, power calculations, and outcome measures in clinical trials

Objective: To assess efficacy and durability (using Orthostatic Hypotension Symptom Assessment [OHSA] and OH Daily Activities Scale [OHDAS]), and safety of ampreloxetine, once-daily to treat neurogenic orthostatic hypotension (nOH) in subjects with synucleinopathies.
Background(s): Failure of the autonomic nervous system results in nOH with inadequate increase in synaptic norepinephrine (NE) and maintenance of upright blood pressure (BP) following postural change. Ampreloxetine is a novel norepinephrine reuptake inhibitor being investigated for treatment of symptomatic nOH.
Method(s): In a 24-week open-label phase 2 multicenter study of subjects with nOH, following a single-dose escalation phase, responders were treated with oral ampreloxetine (3-20 mg) once-daily for up to 20 weeks with 4-week follow-up after treatment withdrawal (Week 24). Primary efficacy endpoint OHSA#1 (dizziness, lightheadedness, feeling faint) was assessed at end of Week 4; end of open-label treatment (Week 20); and after treatment withdrawal (Week 24).
Result(s): Twenty-one subjects enrolled in the open-label phase (mean age, 64 years; 57% multiple-system atrophy). Sixteen (76%), 11 (52%), and 10 (48%) subjects completed assessments at Weeks 4, 20, and 24, respectively. Mean (SD) improvement from baseline in OHSA#1 was 2.4 (4.5) and 1.9 (3.1) for all subjects, and 3.8 (3.1) and 3.1 (3.0) for symptomatic subjects (OHSA#1 C4 at baseline) at Weeks 4 and 20, respectively, scores were back to baseline levels at Week 24. Similar trends in improvement were observed in OHSA and OHDAS composite scores. Most common adverse events (AEs) were urinary tract infection (24%), hypertension (19%), and headache (14%). Two subjects (10%) discontinued treatment due to AEs and 5 (24%) reported serious AEs, none considered related to study medication.
Conclusion(s): In subjects with nOH, ampreloxetine demonstrated clinically meaningful improvement in OHSA#1 at Week 4, which was sustained over 20 weeks, and reverted to baseline after treatment withdrawal. Similar trends were observed in OHSA and OHDAS composite scores. Ampreloxetine was well-tolerated

Objective: We present the protocol, recruitment numbers, and preliminary adverse event profile of patients enrolled in a single-center phase-2 futility trial using sirolimus for multiple system atrophy (MSA) (ClinicalTrials.gov: NCT03589976).
Background(s): In patients with MSA, autophagy is impaired and misfolded aSyn accumulates in neurons and glia, causing neurodegeneration. Sirolimus, a medication that has been approved by the U.S. Food and Drug Administration for chronic treatment in humans for a variety of disorders for almost 20 years, is a potent activator of autophagy. We hypothesize that treatment with sirolimus might activate autophagy of aSyn resulting in reduced neurodegeneration and slower progression of the neurological deficits in patients with MSA.
Method(s): Single-center, randomized, placebo-controlled, phase-2 futility clinical trial to determine if sirolimus is of sufficient promise to slow the disease progression of patients with MSA, prior to embarking on a large-scale and costly phase-3 study to assess its efficacy. Non-futility will offer strong support for a phase-3 trial to detect clinical efficacy. We will enroll 56 patients with a 3:1 (sirolimus:placebo) randomization. We expect to complete enrollment in 2 years.
Result(s): The first patient was screened and enrolled in September 2018. By May 2019, 35 patients had been screened and 31 had been enrolled and randomized. By October 2019 we expect to have enrolled 43 patients (76% of our final target enrollment). Common adverse events included oral ulcers, abdominal discomfort and diarrhea/loose stools. Recruitment and adverse events will be updated by the time of this abstract presentation.
Conclusion(s): This is the first time sirolimus or analogs are being used clinically with the aim of slowing disease progression in patients with neurodegenerative disorders. Our observations may offer strong support for a phase-3 trial to confirm the efficacy of sirolimus in MSA