Faculty Bibliography

Background: Stress-induced adrenergic hypertensive crises are a cardinal feature of familial dysautonomia (FD). Classically, this is treated with clonidine and benzodiazepines, which cause excessive sedation and can lead to respiratory arrest. Dexmedetomidine is a recently introduced compound, 8 times more specific for central alpha-2 adrenergic receptors than clonidine, resulting in less sedation. Advantages over clonidine are also that dexmedetomidine can be administered intravenously (IV), and its half-life is shorter (12 vs. 2 h), which allows an easy titration.
Method(s): Retrospective chart review of IV dexmedetomidine use to treat refractory hypertensive crisis in patients with FD.
Result(s): IV dexmedetomidine was used 15 times in 9 patients (mean age: 26 years; 44 % men) with acute adrenergic crisis. Crisis triggers included respiratory infection (n = 8), emotional stress (n = 3), surgery (n = 1), bacteremia (n = 1), gastroenteritis (n = 1) and bleeding gastric ulcer (n = 1). Before treatment, all patients had signs of adrenergic activation including skin flushing, nausea/retching, vomiting, diaphoresis, and agitation. Blood pressure (BP) was 1616/1026 mmHg and heart rate (HR) was 1134 bpm. IV dexmedetomidine was administered at an average rate of 0.510.13 mcg/kg/h. One hour post-infusion, BP decreased to 1165/586 mmHg (p<0.0001) and HR to 975 bpm (p = 0.002). Drowsiness occurred in one patient, although he was easily arousable. There were no episodes of rebound hypertension or respiratory depression. In one case, rapid titration at a high dose resulted in paradoxical hypertension, which subsided immediately upon dexmedetomidine discontinuation.
Conclusion(s): IV dexmedetomidine is an effective, well-tolerated approach for managing adrenergic crises in patients with FD. In contrast to other commonly used medications, dexmedetomidine does not induce excessive sedation or respiratory depression. In a small percentage of patients, rapid IV dosing may result in paradoxical hypertension due to its direct action on peripheral postsynaptic alpha2-adrenergic receptors

Introduction: Patients with afferent or efferent lesions in the arterial baroreflex pathways can have orthostatic hypotension, but only those with afferent lesions have stress-induced paroxysmal hypertension. The effect of these different abnormalities on circadian blood pressure (BP) and heart rate (HR) profiles has not been systematically compared.
Method(s): We prospectively collected 24-h ambulatory BP and HR recordings in 50 patients with afferent lesions (6 acquired and 44 developmental due to familial dysautonomia). We compared this with recordings obtained in 51 patients with efferent lesions (40 with Lewy body disorders and 11 with multiple system atrophy). A similar number of patients in both groups were taking fludrocortisone (25 %) and midodrine (37 %). Thirty-six percent of patients with afferent lesions were taking clonidine. Differences in age, medications, and diagnosis were used as co-variants.
Result(s): Patients with afferent lesions were younger, had lower average 24-h, daytime, and nighttime systolic (p<0.0001, p = 0.0002, p<0.0001) and diastolic blood pressures (p = 0.006, p = 0.085, p = 0.0001). However, with age as a covariant, these differences were not significant. HR was consistently higher in patients with afferent lesions (p<0.0001). Variability of both diastolic BP (STD 19.35.9 vs. 12.63.9 mmHg, p<0.0001) and HR (STD 11.53.5 vs. 8.54.2 bpm, p = 0.0003) were higher in patients with afferent lesions, and this was still significant with age and clonidine use as co-variants. Patients with afferent lesions had at least one diastolic hypertensive surge that was higher than those captured in patients with efferent lesions (11625 vs. 10516 mmHg, p = 0.009). Nighttime BP dipping (i.e., a fall >10 %) was present in 46 % patients with afferent lesions and only in 19 % of those with efferent lesions. Excluding patients taking clonidine did not change the significance of the results.
Conclusion(s): Patients with afferent lesions of the baroreflex have higher variability in BP and HR over a 24-h period than those with efferent lesions. Unstable blood pressure is a known risk factor for target organ damage. As these patients frequently have early onset renal disease, prospective trials to reduce blood pressure variability are warranted

We previously reported that the norepinephrine transporter inhibitor, atomoxetine, improves upright blood pressure and pre-syncopal symptoms as measured by the orthostatic hypotension symptom assessment (OHSA) in patients with neurogenic orthostatic hypotension (nOH). The purpose of this study was to determine the predictors of the improvement in orthostatic symptoms with atomoxetine. Our sample size consisted of 101 autonomic failure patients with nOH who participated in clinical trials (NCT00223691, NCT1316666) conducted in two national referral centers for autonomic disorders (Vanderbilt Autonomic Dysfunction Center and NYU Langone Medical Center Dysautonomia Center). The analysis was performed in patients with symptomatic nOH defined as item-1 OHSA (lightheadedness) equal or more than four points. Seated blood pressure was measured in three occasions before and 60 min after receiving 18 mg of atomoxetine. Standing blood pressure at 1, 3, 5 and 10 min and OHSA questionnaire was collected before and after the atomoxetine dose. Multiple linear regression was used to test for overall linear relations between the dependent variable (OHSA score after atomoxetine) and independent variables (baseline OHSA score, age, diagnosis, baseline supine norepinephrine levels) and to assess the significance of these relations after adjustments for each covariate.
Result(s): 47 patients (47 %) met criteria for symptomatic nOH. The average age at the time of evaluation was 67 +/- 9 years, 47 % were males. 55 % were diagnosed as pure autonomic failure, 30 % as multiple system atrophy, 11 % as Parkinson disease and 4 % were patients with nOH of unknown etiology. Adjusted R2 for this model was 0.3, only supine norepinephrine levels (P = 0.047) accurately predicted orthostatic symptoms following atomoxetine after adjusting for baseline OHSA, age and specific diagnosis.
Conclusion(s): Supine baseline norepinephrine levels predict the improvement in symptoms produced by atomoxetine in patients with symptomatic nOH

Background: In synucleinopathies, deposits of alpha-synuclein occur in sympathetic neurons innervating sweat glands, leading to impaired sudomotor function. Hence, measurement of sweat production may be relevant as a diagnostic biomarker. We hypothesized that patients with synucleinopathies have decreased electrodermal activity, and that this is associated with sympathetic adrenergic impairment.
Objective(s): To evaluate electrodermal activity in subjects with synucleinopathies.
Method(s): Cross-sectional study including 106 patients with synucleinopathies (55 with idiopathic Parkinson disease-PD-, 18 with probable multiple system atrophy-MSA-, 25 with pure autonomic failure-PAF-, and 8 with idiopathic REM behavior disorder-RBD-) and 57 healthy controls enrolled in New York University (New York, NY) and Hospital de Cruces (Bilbao, Spain). Electrodermal activity was assessed with a device (Sudoscan). Standard cardiovascular autonomic testing (in all subjects) and I¹²³metaiodobenzylguanidine myocardial scintigraphy (in 30 patients with PD) were performed to quantify sympathetic adrenergic dysfunction.
Result(s): Electrodermal activity both in the palms and in the soles was lower in patients than in controls (p<0.01). When considered separately, MSA, PAF and RBD had lower electrodermal activity in the palms than in controls (p<0.001), whereas electrodermal activity in the soles was lower in MSA, PAF and PD (p<0.05). Linear regressions showed that reduced electrodermal activity was associated with markers of sympathetic adrenergic impairment (p<0.05), but not with disease duration.
Conclusion(s): Decreased electrodermal activity in palms and soles is a frequent finding in synucleinopathies. Decreased electrodermal activity was associated with decreased sympathetic adrenergic function, suggesting a parallel degeneration of both adrenergic and cholinergic sympathetic fibers

Background: Pure autonomic failure is a neurodegenerative synucleinopathy largely restricted to the peripheral nervous system. Later in the clinical course of the disease some patients may develop parkinsonism, cerebellar ataxia or cognitive impairment. The purpose of this study is to define the clinical features and biomarkers that predict which patients will retain a pure autonomic failure phenotype, and which will develop clinical deficits indicating spread of the synucleinopathy to the central nervous system.
Method(s): One hundred patients with pure autonomic failure were recruited at 5 medical centers in the US. Participants were followed at 12-months intervals, for 4 years to determine whether they had developed motor/cognitive abnormalities and met the diagnostic criteria of Parkinson disease (PD)/dementia with Lewy bodies (DLB) or multiple system atrophy (MSA). Smell discrimination, occurrence of REM sleep behavior disorder (RBD) and sympathetic and parasympathetic cardiovascular autonomic functions were assessed.
Finding(s): Mean age of onset of autonomic failure was 61 (+/-12) years. Patients had a 10 % per year cumulative risk for developing a CNS synucleinopathy with locomotor dysfunction or dementia. All patients who developed a CNS synucleinopathy had subtle motor impairment and RBD at the time of enrolment. Factors that predicted a future diagnosis of MSA included younger age at onset of autonomic failure, severe bladder/bowel abnormalities, normal olfaction and a >10 bpm cardiac chronotrophic response to tilt. Factors that predicted future diagnosis of PD/DLB were abnormal olfaction, a lesser chronotrophic response to tilt and longer disease duration. Patients that retained a PAF phenotype had very low circulating norepinephrine levels, slow resting heart rate, no RBD or subtle motor deficits and preserved smell discrimination.
Interpretation(s): Pure autonomic failure can be a premotor stage of a central nervous system synucleinopathy or may remain as a restricted peripheral disorder. Patients who developed PD/DLB or MSA have distinct premotor features. Patients who retain a pure autonomic failure phenotype had more severe peripheral sympathetic involvement

Droxidopa, a synthetic norepinephrine precursor, was recently approved to treat symptomatic neurogenic orthostatic hypotension (nOH). The pressor response is variable with some patients responding to doses of 100 mg while others requiring up to 600 mg three times/day. It is not known which factors predict the magnitude of the pressor response to droxidopa. We prospectively evaluated the BP response to increasing doses of droxidopa in patients with nOH in an outpatient setting. BP supine and after 3-min standing was measured before and 1-h after oral administration of 100 mg of droxidopa. Droxidopa was progressively increased until (i) complete relief of symptoms, (ii) supine systolic BP >180 mmHg, (iii) occurrence of side effects, or (iv) the maximum dose of 600 mg was reached. Sixteen subjects with nOH (6 with Parkinson disease, 5 with pure autonomic failure, 3 with autoimmune autonomic ganglionopathy, and 2 with multiple system atrophy) were evaluated. Mean BP was 126 +/- 28/72 +/- 11 mmHg supine, and 89 +/- 19/ 53 +/- 15 mmHg after 3-min standing (fall of 37/18 mmHg). Mean plasma norepinephrine while supine was 192 +/- 216 pg/ml. Maximum droxidopa dose during the titration was 212 +/- 102 mg (range 100-400 mg). Droxidopa increased BP to an average of 148 +/- 53/ 90 +/- 13 mmHg supine and 135 +/- 38/66 +/- 16 mmHg after 3-min standing (p<0.001). Plasma norepinephrine levels were inversely correlated with higher systolic BP after 3-min standing following droxidopa treatment (R2 = 0.42; p = 0.023). Four patients (3 with AAG and 1 with PAF) with very low plasma norepinephrine levels (<90 pg/ml) experienced transient nausea, vomiting, and abdominal pain during titration with dosages of 200 mg. In these patients, treatment with 100 mg/day was effective and well tolerated. Diagnostic categories did not predict response to droxidopa. In patients with nOH, lower plasma norepinephrine levels are associated with a greater pressor response to droxidopa. This response is probably related to the degree of denervation supersensitivity. Supine norepinephrine levels may be useful to predict appropriate dosing of droxidopa in a clinical setting

Background: Patients with familial dysautonomia (FD) have asthmalike exacerbations with coughing, wheezing, and hypoxia. While many are treated empirically with bronchodilators, it is still unknown whether airway obstruction in these patients is pharmacologically reversible by modifying autonomic tone.
Method(s): We conducted a two-center, randomized, placebo-controlled, double blind, crossover study to assess the safety and efficacy of albuterol (a direct acting sympathomimetic) vs. ipratropium bromide (a parasympatholytic muscarinic blocker). Albuterol (0.083 %, 2.5 mg/3 ml), ipratroprium bromide (0.02 %, 500 mcg/2.5 ml) and placebo (0.9 % sodium chloride 3 ml) were administered by nebulization in random order over 15 min in the seated position. Airway responses were assessed with spirometry and impulse oscillometry pre- and 30 min post-dose. Continuous blood pressure, RR-intervals and cardiac impedance were measured non-invasively (TaskForce Monitor, CNSystems, Graz, Austria). Raw data tracings were analyzed blindly.
Result(s): Fifteen patients were enrolled. All had a documented history of aspiration into the airway and acute episodes of coughing and wheezing. Beta-adrenergic activation with albuterol significantly increased forced vital capacity (p = 0.041) and forced expiratory volume within 1 s (p = 0.002). In line with this, impulse oscillometry at 5 Hz was significantly lower post-albuterol (p = 0.006), suggesting a reduction in total airway resistance. Blockade of muscarinic acetylcholine receptors with ipratroprium had less bronchodilatory effects. Both treatments were well tolerated and had no effects on blood pressure, heart rate or derived cardiac output.
Conclusion(s): In patients with FD, beta-adrenergic stimulation more effectively reversed airway obstruction than muscarinic blockade. Both treatments were well tolerated and had no measureable systemic effects

The prodrug droxidopa increases blood pressure (BP) in patients with neurogenic orthostatic hypotension. The BP profile of droxidopa in neurogenic orthostatic hypotension patients (n = 18) was investigated using ambulatory BP monitoring. Following dose optimization and a washout period, 24-hour "off-drug" data were collected. "On-drug" assessment was conducted after 4-5 weeks of droxidopa treatment (mean dose, 444 mg, three times daily). Ambulatory monitoring off drug revealed that 90% of patients already had abnormalities in the circadian BP profile and did not meet criteria for normal nocturnal BP dipping. On treatment, both overall mean 24-hour systolic and diastolic BPs were higher compared to off drug (137/81 mm Hg vs. 129/76 mm Hg; P = .017/.002). Mean daytime systolic BP was significantly higher with droxidopa (8.4 +/- 3.1 mm Hg; P = .014). Although nocturnal BP was not significantly higher on droxidopa versus off treatment (P = .122), increases in nocturnal (supine) BP >/=10 mm Hg were observed in four cases (22%). Severe supine systolic hypertensive readings at night (>200 mm Hg) were captured in one case and only while on treatment. These data demonstrate that ambulatory BP monitoring is useful to evaluate the circadian BP profile after initiating treatment with a pressor agent.