Faculty Bibliography

Background: Multiple system atrophy (MSA) is a fatal and poorly understood rare neurodegenerative disorder. Here we describe the baseline characteristics of patients with MSA enrolled in a prospective multicenter natural history study of the NIH-sponsored U.S. Autonomic Disorders Consortium. Methods: Patients with a clinical diagnosis of MSA were prospectively enrolled at 5 participating centers. Demographic data, clinical variables, and autonomic testing results were included. Results: One hundred and nine patients with MSA (45 women) have been enrolled. MSA-C was predominant (60 patients, 55%). Mean age at symptom onset was 56.5 +/- 8.8 and at enrollment was 61.2+/-8.04 years old. Mini Mental score was 28.9 +/-1.4 indicating normal cognition. Both the E:I ratio (1.09+/-0.08) and the Valsalva ratio (1.24+/-0.28) were low, indicating cardiovagal impairment. In the supine position, blood pressure (SBP/

Familial dysautonomia (FD) features a unique combination of cardiovascular disturbances not seen in patients with any other chronic disorder of the autonomic nervous system. While blood pressure falls and both heart rate and plasma noradrenaline fail to increase during standing in FD, patients demonstrate significant increases in blood pressure and plasma noradrenaline during episodes of emotional arousal. This indicates that vasoconstrictor neurones can be activated during states of emotional arousal, and that noradrenaline is released. Because constriction of arterioles in skeletal muscle vascular beds is one of the primary determinants of total peripheral resistance and hence of blood pressure, we would expect that muscle sympathetic nerve activity (MSNA) -which is vasoconstrictor in function - would be present in patients with FD. However, given the absence of functional baroreflex afferents we predicted that MSNA would not appear as cardiac-locked bursts. We tested this hypothesis using tungsten microelectrodes inserted percutaneously into muscle or cutaneous fascicles of the nerve in 12 patients with FD. Spontaneous bursts of MSNA were absent in all patients, but in five patients we found evidence of tonically firing sympathetic neurones, with no cardiac rhythmicity, that increased their spontaneous discharge during emotional arousal but not during baroreceptor unloading. Conversely, skin sympathetic nerve activity (SSNA) appeared normal. We conclude that the loss of baroreflex modulation of MSNA contributes to the poor control of blood pressure in FD, and that the increase in tonic firing of muscle vasoconstrictor neurones contributes to the increase in blood pressure during emotional excitement

Background: Familial dysautonomia (FD) is a rare genetic disorder affecting the development of sensory and autonomic neurons. Patients with FD have impaired ventilatory responses to hypoxia and hypercapnia. The disease is associated with an increased risk of sudden death, particularly during sleep. Aim: To define sleep structure and respiratory function during sleep in FD. Methods: Cross-sectional study of 63 patients with FD that underwent fullnight polysomnography (age 17 +/- 12 years, range 2-50, 30 women). Information on sleep structure, apnea hypopnea index (AHI), oxygen saturation and periodic limb movement index (PLMI) was assessed. Data on EtCO2 was available in 9 subjects. Results: Total sleep time was 361 +/- 110 minutes. Sleep efficiency 78 +/- 14%; REM latency 114 +/- 85 min. Time spent in REM sleep was 20 +/- 11%. The mean heart rate (HR) was 82 +/- 16 bpm. Maximum HR was 128 +/- 31 bpm and the minimum was 58+/- 13 bpm. Average AHI was 11.4 +/- 12 events/h. Thirty-one patients had an AHI < 4; 11 patients had an AHI 5-15; 16 patients had an AHI 15-30; and 4 patients had an AHI > 30. Mean oxygen saturation was 96.6+/- 2.8%. Mean minimum (nadir) oxygen saturation was 58.5 +/- 43%. Average % of time spent with an oxygen saturation < 90% was 9.3 +/- 18%. Mean EtCO2 was 44.1 +/- 5.1 mmHg; maximum EtCO2 was 50.9 +/- 9.4 mmHg. PLM index was 0.14+/- 0.7 events/h. Conclusions: This is the largest series of sleep studies in FD and confirms that sleep disordered breathing (sleep apnea and sleep-related hypoventilation) is highly prevalent. Sleep structure was preserved and none of the patients exhibited periodic limb movements

Background: Sudden death during sleep is the leading causes of death in patients with familial dysautonomia (FD). Patients with FD have impaired ventilatory responses to hypoxia and hypercapnia and sleep disordered breathing, but it is unclear whether these are associated with sudden death. Aim: To identify features that are associated with sudden death during sleep in FD. Methods: We retrospectively selected patients who died suddenly during sleep and compared their sleep studies, arterial blood gases and ECG, performed within 1-year prior to death with those of FD subjects that were alive. Results: Of 108 patients that died suddenly during sleep, 32 had a sleep study, arterial blood gases and ECG performed within 1-year prior to death. Similar information was available in 23 patients with FD that were alive. There were no significant differences in the apnea hypopnea index (p= 0.10), average heart rate (p=0.30) or other ECG parameters. The average lowest oxygen saturation during sleep was not different either (p =0.17), although in 7 deceased patients oxygen saturation fell below 60% while in none of the alive group fell as low. The arterial HCO3 levels were significantly higher in the deceased group (p= 0.005) although there were no differences in average pCO2 levels (p=0.10). Conclusions: FD patients that died suddenly during sleep had a propensity toward more pronounced nocturnal oxygen desaturations and had significantly higher levels of plasma HCO3 suggesting compensatory metabolic alkalosis

Patients with familial dysautonomia (FD) have afferent baroreflex failure and often experience extremely low blood pressure when upright, but rarely complain of symptoms of hypoperfusion. This suggests that patients either fail to recognize cerebral ischemia or have a better than normal cerebrovascular auto-regulatory capacity. Our aim was to examine the relationship between blood pressure, cerebral blood flow, and orthostatic symptoms in FD patients. We measured continuous blood pressure, RR intervals, end-tidal carbon dioxide and middle cerebral artery blood flow velocity (transcranial Doppler) supine, sitting, and standing in eleven patients with FD (age 27+/-2 years, 5males) and seven age-matched controls. Subjects were asked to report the presence or absence of symptoms at one-minute intervals. In patients with FD, systolic blood pressure fell significantly from 137+/-8 mmHg to 105 +/- 9 mmHg after 3 minutes of standing (p < 0.006, range 55 to 149 mmHg). Despite the fall in blood pressure none of the patients reported symptoms of orthostatic hypotension. Changes in cerebral blood flow were minimal (mean DELTA-6+/-3%), and not statistically different to controls (DELTA-3+/- 2%, p=0.39), which maintained their blood pressure well on standing. The results show that patients with FDhave an excellent auto-regulatory capacity and maintain cerebral blood flow within the normal range despite severe hypotension. This study highlights the usefulness of cerebral blood flow recordings to understand the relationship between symptoms and blood pressure in patients with abnormal baroreflex function

Neurogenic orthostatic hypotension (nOH) is a fall in blood pressure on standing due to impaired norepinephrine release from postganglionic sympathetic neurons. nOHmay cause disabling hypoperfusion of the brain and other tissues. Non-pharmacological measures are the first line of treatment and include pressure garments and new types of abdominal binders. Pharmacological approaches include intravascular volume expansion and pressor agents. Recently, large, international phase 3 clinical trials of droxidopa (Northera) an artificial aminoacid converted to norepinephrine by dopa decarboxylase, showed significant symptomatic improvement in patients with nOH and led to droxidopa's approval by the United States Food and Drug Administration. This successful strategy was similar to dopamine replacement therapy in Parkinson disease (PD) with l-dopa. Concomitant administration of 200 mg carbidopa, a dopa decarboxylase inhibitor that does not cross the blood brain barrier, blocks the pressor effect of droxidopa but only at doses higher than those used clinically. Atomoxetine a norepinephrine reuptake inhibitor, also increased blood pressure in patients with nOH and reduced symptoms of orthostatic hypotension in a small, single-dose trial. Combining droxidopa with inhibitors of other enzymes/transporters involved in catecholamine metabolism, as has been tried with levodopa in PD, is an attractive therapeutic strategy to explore. Potential treatment options to investigate in nOH also include the use of a2-adrenoreceptor antagonists thought to increase the release of NE from remaining sympathetic postganglionic neurons

OBJECTIVE: Congenital insensitivity to pain with anhidrosis (CIPA) is caused by mutations in the NKTR1 gene. This affects the development of nerve growth factor (NGF)-dependent neurons including sympathetic cholinergic neurons in the skin, causing anhidrosis. Cardiovascular and blood pressure regulation appears normal, but the integrity of sympathetic adrenergic neurons has not been tested. METHODS: We examined the effect of posture on blood pressure, heart rate, plasma concentration of catecholamines, vasopressin, endothelin, and renin activity in 14 patients with CIPA, 10 patients with chronically deficient sympathetic activity (pure autonomic failure), and 15 normal age-matched controls. RESULTS: In all 14 patients with CIPA, plasma norepinephrine levels were very low or undetectable and failed to increase when the patient was upright, yet upright blood pressure was well maintained. Plasma epinephrine levels were normal and increased when the patient was upright. Plasma renin activity also increased appropriately when the patient was upright and after furosemide-induced volume depletion. Nitric oxide-mediated endothelial function was intact. Patients with pure autonomic failure also had very low levels of plasma norepinephrine both supine and upright, but in contrast to patients with CIPA failed to maintain blood pressure upright. INTERPRETATION: The results indicate that postganglionic sympathetic neurons are severely depleted in CIPA, but chromaffin cells of the adrenal medulla are spared. This confirms the differential effect of NGF signaling for sympathetic neural and chromaffin cell development. The finding that patients with CIPA maintain blood pressure well on standing challenges current concepts of the role of norepinephrine in the regulation of arterial pressure. Ann Neurol 2015;77:743-752.