Faculty Bibliography

OBJECTIVE: To define the clinical features and biomarkers that predict which patients with pure autonomic failure will develop Parkinson disease, dementia with Lewy bodies, or multiple system atrophy. METHODS: One hundred patients who presented with pure autonomic failure were recruited at 5 medical centers in the U.S. Seventy-four patients agreed to be followed prospectively. Patients underwent clinical evaluations including neurological rating scales, sleep questionnaires, smell test, and sympathetic and parasympathetic cardiovascular autonomic function tests. RESULTS: At enrollment, patients were 68(12) years old [(median (interquartile range)] and had had autonomic failure for 5(7) years. Within 4-years of follow-up, 25 of 74 subjects (34%) developed dementia with Lewy bodies (in 13), Parkinson disease (in 6), or multiple system atrophy (in 6). The presence of probable REM sleep behavior disorder was strongly associated with the development of a manifest CNS synucleinopathy (odds ratio=7.1). Patients who phenoconverted to multiple system atrophy had younger age at onset of autonomic failure, severe bladder/bowel dysfunction, preserved olfaction, and a cardiac chronotrophic response upon tilt >10 beats per minute. Those who phenoconverted to Parkinson disease or dementia with Lewy bodies had decreased olfaction, a lesser chronotrophic response to tilt, and a longer duration of illness. The small group of patients retaining the pure autonomic failure phenotype had very low plasma norepinephrine levels, slow resting heart rate, no REM sleep behavior disorder, and preserved smell. INTERPRETATION: Patients presenting with pure autonomic failure are at high risk of phenoconverting to a manifest CNS synucleinopathy. Specific clinical features predict future diagnosis

Neurogenic orthostatic hypotension (nOH) is common in patients with neurodegenerative disorders such as Parkinson's disease, multiple system atrophy, pure autonomic failure, dementia with Lewy bodies, and peripheral neuropathies including amyloid or diabetic neuropathy. Due to the frequency of nOH in the aging population, clinicians need to be well informed about its diagnosis and management. To date, studies of nOH have used different outcome measures and various methods of diagnosis, thereby preventing the generation of evidence-based guidelines to direct clinicians towards 'best practices' when treating patients with nOH and associated supine hypertension. To address these issues, the American Autonomic Society and the National Parkinson Foundation initiated a project to develop a statement of recommendations beginning with a consensus panel meeting in Boston on November 7, 2015, with continued communications and contributions to the recommendations through October of 2016. This paper summarizes the panel members' discussions held during the initial meeting along with continued deliberations among the panel members and provides essential recommendations based upon best available evidence as well as expert opinion for the (1) screening, (2) diagnosis, (3) treatment of nOH, and (4) diagnosis and treatment of associated supine hypertension.

OBJECTIVE: Adrenergic crises are a cardinal feature of familial dysautonomia (FD). Traditionally, adrenergic crises have been treated with the sympatholytic agent clonidine or with benzodiazepines, which can cause excessive sedation and respiratory depression. Dexmedetomidine is a centrally-acting alpha 2-adrenergic agonist with greater selectivity and shorter half-life than clonidine. We evaluated the preliminary effectiveness and safety of intravenous dexmedetomidine in the treatment of refractory adrenergic crisis in patients with FD. METHODS: Retrospective chart review of patients with genetically confirmed FD who received intravenous dexmedetomidine for refractory adrenergic crises. The primary outcome was preliminary effectiveness of dexmedetomidine defined as change in blood pressure (BP) and heart rate (HR) 1 h after the initiation of dexmedetomidine. Secondary outcomes included incidence of adverse events related to dexmedetomidine, hospital and intensive care unit (ICU) length of stay, and hemodynamic parameters 12 h after dexmedetomidine cessation. RESULTS: Nine patients over 14 admissions were included in the final analysis. At 1 h after the initiation of dexmedetomidine, systolic BP decreased from 160 +/- 7 to 122 +/- 7 mmHg (p = 0.0005), diastolic BP decreased from 103 +/- 6 to 65 +/- 8 (p = 0.0003), and HR decreased from 112 +/- 4 to 100 +/- 5 bpm (p = 0.0047). The median total adverse events during dexmedetomidine infusion was 1 per admission. Median hospital length of stay was 9 days [interquartile range (IQR) 3-11 days] and median ICU length of stay was 7 days (IQR 3-11 days). CONCLUSIONS: Intravenous dexmedetomidine is safe in patients with FD and appears to be effective to treat refractory adrenergic crisis. Dexmedetomidine may be considered in FD patients who do not respond to conventional clonidine and benzodiazepine pharmacotherapy.

Familial dysautonomia is an inherited autonomic disorder with afferent baroreflex failure. We questioned why despite low blood pressure standing, surprisingly few familial dysautonomia patients complain of symptomatic hypotension or have syncope. Using transcranial Doppler ultrasonography of the middle cerebral artery, we measured flow velocity (mean, peak systolic, and diastolic), area under the curve, pulsatility index, and height of the dictrotic notch in 25 patients with familial dysautonomia and 15 controls. In patients, changing from sitting to a standing position, decreased BP from 124 +/- 4/64 +/- 3 to 82 +/- 3/37 +/- 2 mmHg (p < 0.0001, for both). Despite low BP, all patients denied orthostatic symptoms. Middle cerebral artery velocity fell minimally, and the magnitude of the reductions were similar to those observed in healthy controls, in whom BP upright did not fall. While standing, patients had a greater fall in cerebrovascular resistance (p < 0.0001), an increase in pulsatility (p < 0.0001), and a deepening of the dicrotic notch (p = 0.0010), findings all consistent with low cerebrovascular resistance. No significant changes occurred in controls. Patients born with baroreflex deafferentation retain the ability to buffer wide fluctuations in BP and auto-regulate cerebral blood flow. This explains how they can tolerate extremely low BPs standing that would otherwise induce syncope.

Familial dysautonomia (FD) is a rare neurological disorder caused by a splice mutation in the IKBKAP gene. The mutation arose in the 1500s within the small Jewish founder population in Eastern Europe and became prevalent during the period of rapid population expansion within the Pale of Settlement. The carrier rate is 1:32 in Jews descending from this region. The mutation results in a tissue-specific deficiency in IKAP, a protein involved in the development and survival of neurons. Patients homozygous for the mutations are born with multiple lesions affecting mostly sensory (afferent) fibers, which leads to widespread organ dysfunction and increased mortality. Neurodegenerative features of the disease include progressive optic atrophy and worsening gait ataxia. Here we review the progress made in the last decade to better understand the genotype and phenotype. We also discuss the challenges of conducting controlled clinical trials in this rare medically fragile population. Meanwhile, the search for better treatments as well as a neuroprotective agent is ongoing.

The ability of the skin to conduct electricity depends on sweat secretion. This is referred to as electrodermal or electrochemical skin conductance. Recently, a technique has been developed to assess electrodermal activity using reverse iontophoresis dependent on sweat chloride levels. This method can reliably identify patients with cystic fibrosis, a disease with well-described increases in chloride concentration in sweat. Our goal was to determine the relationship between electrodermal response and serum chloride levels in other patient groups. We conducted a cross-sectional study involving 38 subjects with HSAN-III (familial dysautonomia, FD) and 20 healthy controls. Electrodermal activity of the soles was assessed using stainless steelbased plate electrodes applied under the soles of the feet for 3 min (Sudoscan). The influence of age, serum electrolyte levels, and medications were analyzed.
Result(s): Electrodermal activity was normal (>60 microS) in 24 patients (63 %) and reduced (<60 microS) in the remaining 14. There was a direct correlation between electrodermal activity and serum chloride levels (p = 0.007). Reduced electrodermal activity was explained by low serum chloride in 6 patients, and likely by medications in 8 (clonidine). All controls had normal electrodermal activity, but because their serum chloride levels were normal in every subject (>97 mEq/L), no correlation could be established.
Conclusion(s): Low serum chloride levels result in reduced electrodermal activity. In addition to medications, serum chloride levels should be checked to properly interpret electrodermal activity measurements

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

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