Faculty Bibliography

Background: Normally, during sleep, when cortical influences are minimized, blood pressure (BP) and heart rate (HR) fall (i.e., nocturnal dipping). In patients with afferent baroreflex failure, in whom BP and HR are highly dependent on cortical influences, this nocturnal dipping is usually preserved. There are, however, a number of patients with afferent baroreflex failure in whom BP does not dip at night. The reasons for this are unknown.
Method(s): We examined the 24-hour ambulatory BP profiles in 50 patients with afferent baroreflex failure of acquired (n = 6) or genetic origin (familial dysautonomia n = 44). BP and HR were captured at 30-minute intervals over a 24-h period. Nighttime sleep periods were identified from the patient's diary. Dipping was defined as a 10 % or greater fall in systolic and diastolic blood pressure at night.
Result(s): Normal BP nocturnal dipping was present in only 50 % of the patients; 33 % of patients had reversal of the circadian rhythm with higher blood pressures at night. In the remaining 17 %, nocturnal BP was similar to daytime BP. Patients with preserved nocturnal dipping had a significantly higher glomerular filtration rate (8430 mL/ min) than those that did not dip at night (6130 mL/min, p = 0.043).
Conclusion(s): Lack of nocturnal BP dipping in patients with afferent baroreflex failure was associated with impaired renal function. These findings suggest that in patients with FD, a non-dipping profile may involve abnormalities in extracellular volume and/or impaired regulation of vascular resistance (i.e., abnormal endothelial function)

Background: Infusion of vasoactive agents in the assessment of orthostatic intolerance in the autonomic laboratory is controversial. The technique of lower body negative pressure (LBNP) was described two decades ago. LBNP exaggerates orthostatic stress by closely mimicking a physiologic stimulus, and has the advantage of being quickly reversible. However, it is not routinely used in clinical practice.
Objective(s): To describe our experience using LBNP in the clinical autonomic laboratory in patients with orthostatic intolerance of unclear origin.
Method(s): We used a customized airtight cover, sealed to a tilttable and to the subject at the level of the iliac crest. After 30 min of asymptomatic passive head-up tilt, LBNP was applied while the patient was still upright. Suction was briefly initiated at -20 mmHg for 1-min and then increased to -40 mmHg for the following 10-min. Blood pressure, heart rate and plasma catecholamines when supine, after 10-min of head up tilt, and during syncope or other paroxysmal event, were measured. Time from LBNP onset to episode was recorded.
Result(s): Fifteen subjects (8 men; aged 40 +/- 20 years, range: 12-75 years) were enrolled. During LBNP, 7 subjects developed typical vasovagal syncope (after 3.8 +/- 1.3 min of LBNP) with hypotension and bradycardia and marked increases in plasma levels of epinephrine and vasopressin. Six tolerated the procedure uneventfully. One patient became unresponsive and his head stooped forward but BP and HR remained stable without changes in plasma catecholamines. The remaining patient had flailing bilateral movements with no changes in consciousness, BP or HR, but a significant increase in plasma epinephrine levels. All patients recovered without sequelae.
Conclusion(s): LBNP is a useful technique in the differential diagnosis of patients with orthostatic intolerance of unclear origin and can be easily implemented in the clinical setting. In addition to its wellknown value to induce vasovagal syncope, this technique can also be useful to induce psychogenic episodes

Physicians who specialize in autonomic disorders think in terms of orthostasis, synapses, catecholamines, ganglionopathies, and baroreflexes. Patients, on the other hand, inhabit a world of streaming, downloads, hashtags, tweets, and blogs. In an increasingly digital era, if we are to communicate effectively with patients, we must understand their language, including that of social media. The cultural revolution of social media opens new opportunities for autonomic medicine. First, social media can direct patients to specialists who have the expertise to evaluate and treat their disorders when such expertise is not available locally. Listing contact information on reputable dysautonomia websites is an effective way to facilitate these connections, as is creating practice websites to showcase unique expertise and resources. Secondly, online platforms can empower the patient population through education. In clinical practice, we see how frequently patients turn to the Internet for medical information. However, search engines alone are inadequate because of the sheer volume of available information, much of which is unmonitored. Patients can quickly be led down a path of misinformation about their particular condition. Dr. Google is frequently wrong. Moreover, it takes on average 2.5 clicks to get from a headache to a brain tumor. As experts in the field, we have an obligation to participate online in the translation and dissemination of accurate medical information. It is important to consider the demographics of the target audience and how best to reach them, be it Facebook, Twitter, Instagram or Snap Chat. By doing this we can assist patients in understanding their autonomic disorders and managing their symptoms. Thirdly, social media can be an important tool for research. Social media platforms can be used to recruit research subjects with rare disorders and as a tool to promote the need for research funding from the public. Social media is undoubtedly an effective way to spread news and can be used to disseminate new knowledge arising from research, which allows patients to keep abreast of current breakthroughs. Lastly, social media can be leveraged to raise public awareness about autonomic disorders and their treatment, build community, share experiences, and engage patient groups in partnership

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

Congenital insensitivity to pain with anhidrosis (CIPA, also known as hereditary sensory and autonomic neuropathy type IV) is a rare autosomal recessive disorder caused by mutations in the gene encoding for neurotrophic tyrosine kinase receptor type 1, a receptor for nerve growth factor (NTRK1-NGF). We recently described that patients with CIPA have very low or undetectable circulating norepinephrine levels. Since these mutations severely deplete the development of noradrenergic neurons in the periphery, they presumably also affect those in the central nervous system. Patients with CIPA have low IQ and behavioral problems including hyperactivity and reckless impulsivity, likely the result of a central deficiency in norepinephrine. We explored whether treatment with droxidopa, a synthetic norepinephrine precursor, which crosses the blood brain barrier, could improve behavioral features in a patient with CIPA. Our patient was a 29-year-old woman with a classic phenotype and molecular confirmation of a mutation in the NTRK1 gene (c360- 2A >C pathogenic variant). She had symptoms of attention deficit and hyperactivity and scored highly on the adult ADHD self-report scales (Scores Part A: 4/6 and Part B: 9/12). She had high scores in the attentional (17 and 4), motor (21 and 10), and planning (21 and 17) domains of Barratt impulsiveness scale. NICHQ Vanderbilt assessment scale also indicated attention deficits and hyperactivity. After two months treatment with droxidopa (at 400 mg/day), attention and hyperactivity scales scores decreased to the normal range (Scores Part A: 3/6 and Part B: 4/12). Impulsiveness scores assessed by Barratt impulsiveness scales also improved (attentional scores 15 and 11, motor scores 19 and 9 and planning scores 20 and 9). This case report suggests that behavioral deficits might be reversed in patients with CIPA by norepinephrine replenishment therapy. Clinical studies to evaluate the usefulness of droxidopa to treat behavioral problems in CIPA patients are warranted

Autoimmune autonomic ganglionopathy (AAG) is a rare condition characterized by acute-onset generalized autonomic failure. Some of these patients also develop severe sensory and motor deficits. Droxidopa, an oral norepinephrine precursor, has been previously reported as effective treatment of neurogenic orthostatic hypotension (nOH) in one patient with AAG. Here we report our experience using droxidopa to treat symptomatic nOH in 3 patients with suspected AAG. Patient #1 (35-year-old woman) presented with acute-onset recurrent syncope, urinary retention, constipation, dry mouth, and decreased sweating, but no motor or sensory deficits. Patient #2 (11 year-old boy) and patient #3 (43-year-old woman) presented with similar autonomic deficits as well as severe impairment in all sensory modalities, but patient #3 also had severe generalized muscle weakness and had been initially diagnosed with Guillain-Barre syndrome. In all three patients, autonomic testing showed severe nOH confirmed by absent phase IV blood pressure overshoot after release of the Valsalva strain and very low or undetectable plasma norepinephrine levels. Ganglionic acetylcholine receptor antibodies were not detected in any patient. Droxidopa increased blood pressure and improved symptoms in all three patients. After 1 year, patient #1 is still receiving droxidopa 200 mg three times/day with normalization of standing BP, and continued symptomatic improvement. During the initial droxidopa titration, patients #2 and #3 experienced nausea, abdominal pain, and severe hypertension (>180 mmHg) with dosages > 200 mg. Both have now been receiving 100 mg once/day for a year with improvement in orthostatic tolerance and BP, no side effects and no supine hypertension. In conclusion, droxidopa substantially increased blood pressure standing and reduced symptoms of orthostatic hypotension in adult and pediatric patients with suspected acute autonomic ganglionopathy

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