Faculty Bibliography

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

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